2013 ABPM Guidelines

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APBM 2013 GUIDELINES 2013 Ambulatory Blood Pressure Monitoring Recommendations for the Diagnosis of Adult Hypertension, Assessment of Cardiovascular and other Hypertension-associated Risk, and Attainment of Therapeutic Goals Joint Recommendations from the International Society for Chronobiology (ISC), American Association of Medical Chronobiology and Chronotherapeutics (AAMCC), Spanish Society of Applied Chronobiology, Chronotherapy, and Vascular Risk (SECAC), Spanish Society of Atherosclerosis (SEA), and Romanian Society of Internal Medicine (RSIM) Writing Committee: Ramón C. Hermida, 1 Michael H. Smolensky, 2 Diana E. Ayala, 1 and Francesco Portaluppi 3 Reviewing Committee: Juan J. Crespo, 4 Fabio Fabbian, 3 Erhard Haus, 5 Roberto Manfredini, 3 Artemio Mojón, 1 Ana Moyá, 1,6 Luis Piñeiro, 1,7 María T. Ríos, 1,8 Alfonso Otero, 9 Horia Balan 10 and José R. Fernández 1 1 Bioengineering and Chronobiology Laboratories, University of Vigo, Campus Universitario, Vigo, Spain, 2 Cockrell School of Engineering, Department of Biomedical Engineering, The University of Texas at Austin, Austin, Texas, USA, 3 Hypertension Center, University Hospital S. Anna and Department of Medical Sciences, University of Ferrara, Ferrara, Italy, 4 CS Bembrive, Gerencia de Atención Primaria de Vigo, Servicio Galego de Saúde (SERGAS), Vigo, Spain, 5 Department of Pathology and Laboratory Medicine, University of Minnesota, HealthPartners Institute for Education and Research, Regions Hospital, St. Paul, Minnesota, USA, 6 CS Lérez, Gerencia Unica Integrada Pontevedra-Salnés, Servicio Galego de Saúde (SERGAS), Pontevedra, Spain, 7 Internal Medicine Department, Hospital Provincial de Pontevedra, Servicio Galego de Saúde (SERGAS), Pontevedra, Spain, 8 CS A Doblada, Gerencia de Atención Primaria de Vigo, Servicio Galego de Saúde (SERGAS), Vigo, Spain, 9 Nephrology Department, Complejo Hospitalario Universitario, Servicio Galego de Saúde (SERGAS), Ourense, Spain, 10 University of Medicine and Pharmacy, Bucharest, Romania. Correlation between systolic (SBP) and diastolic (DBP) blood pressure (BP) level and target organ damage, cardiovascular disease (CVD) risk, and long-term prognosis is much greater for ambulatory BP monitoring (ABPM) than daytime office measurements. The 2013 ABPM guidelines specified herein are based on ABPM patient outcomes studies and constitute a substantial revision of current knowledge. The asleep SBP mean and sleep-time relative SBP decline are the most significant predictors of CVD events, both individually as well as jointly when combined with other ABPM-derived prognostic markers. Thus, they should be preferably used to diagnose hypertension and assess CVD and other associated risks. Progressive decrease by therapeutic intervention of the asleep BP mean is the most significant predictor of CVD event-free interval. The 24-h BP mean is not recommended to diagnose hypertension because it disregards the more valuable clinical information pertaining to the features of the 24-h BP pattern. Persons with the same 24-h BP mean may display radically different 24-h BP patterns, ranging from extreme-dipper to riser types, representative of markedly different risk states. Classification of individuals by comparing office with either the 24-h or awake BP mean as masked normotensives(elevated clinic BP but normal ABPM), which should replace the terms of isolated officeor white-coat hypertension, and masked hypertensives(normal clinic BP but elevated ABPM) is misleading and should be avoided because it disregards the clinical significance of the asleep BP mean. Outcome-based ABPM reference thresholds for men, which in the absence of compelling clinical conditions are 135/85 mmHg for the awake and 120/70 mmHg for the asleep SBP/DBP means, are lower by 10/5 mmHg for SBP/DBP in uncomplicated, low-CVD risk, women and lower by 15/10 mmHg for SBP/DBP in male and female high-risk patients, e.g., with diabetes, chronic kidney disease (CKD), and/or past CVD events. In the adult population, Address Correspondence to Prof. Ramón C. Hermida, Ph.D., Bioengineering and Chronobiology Labs, University of Vigo; Campus Univer- sitario Vigo, 36310 Spain. Ph.: 34-986-812148; Fax: 34-986-812116; E-mail: [email protected] Prof. Francesco Portaluppi, M.D., Ph.D. Hypertension Center, S. Anna Hospital, Universityof Ferrara; via Savonarola 9, I-44121 Ferrara, Italy. Ph.: 39-0532-236631; Fax: 39-0532-236622; E-mail: [email protected] Reprint Address: Same as above. Submitted August 23, 2012, Returned for revision September 24, 2012, Accepted October 1, 2012 Chronobiology International, 30(3): 355410, (2013) Copyright © Informa Healthcare USA, Inc. ISSN 0742-0528 print/1525-6073 online DOI: 10.3109/07420528.2013.750490 Chronobiol Int Downloaded from informahealthcare.com by 178.60.156.156 on 03/22/13 For personal use only.

Transcript of 2013 ABPM Guidelines

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A P B M 2 0 1 3 G U I D E L I N E S

2013 Ambulatory Blood Pressure Monitoring Recommendations for theDiagnosis of Adult Hypertension, Assessment of Cardiovascular and otherHypertension-associated Risk, and Attainment of Therapeutic Goals

Joint Recommendations from the International Society for Chronobiology (ISC), American Association of MedicalChronobiology and Chronotherapeutics (AAMCC), Spanish Society of Applied Chronobiology, Chronotherapy, andVascular Risk (SECAC), Spanish Society of Atherosclerosis (SEA), and Romanian Society of Internal Medicine (RSIM)

Writing Committee: Ramón C. Hermida,1 Michael H. Smolensky,2 Diana E. Ayala,1 andFrancesco Portaluppi3

Reviewing Committee: Juan J. Crespo,4 Fabio Fabbian,3 Erhard Haus,5 Roberto Manfredini,3

Artemio Mojón,1 Ana Moyá,1,6 Luis Piñeiro,1,7 María T. Ríos,1,8 Alfonso Otero,9 Horia Balan10 andJosé R. Fernández1

1Bioengineering and Chronobiology Laboratories, University of Vigo, Campus Universitario, Vigo, Spain, 2Cockrell School ofEngineering, Department of Biomedical Engineering, The University of Texas at Austin, Austin, Texas, USA, 3HypertensionCenter, University Hospital S. Anna and Department of Medical Sciences, University of Ferrara, Ferrara, Italy, 4CS Bembrive,Gerencia de Atención Primaria de Vigo, Servicio Galego de Saúde (SERGAS), Vigo, Spain, 5Department of Pathology andLaboratory Medicine, University of Minnesota, HealthPartners Institute for Education and Research, Regions Hospital, St. Paul,Minnesota, USA, 6CS Lérez, Gerencia Unica Integrada Pontevedra-Salnés, Servicio Galego de Saúde (SERGAS), Pontevedra,Spain, 7Internal Medicine Department, Hospital Provincial de Pontevedra, Servicio Galego de Saúde (SERGAS), Pontevedra,Spain, 8CS A Doblada, Gerencia de Atención Primaria de Vigo, Servicio Galego de Saúde (SERGAS), Vigo, Spain, 9NephrologyDepartment, Complejo Hospitalario Universitario, Servicio Galego de Saúde (SERGAS), Ourense, Spain, 10University of Medicineand Pharmacy, Bucharest, Romania.

Correlation between systolic (SBP) and diastolic (DBP) blood pressure (BP) level and target organ damage, cardiovasculardisease (CVD) risk, and long-term prognosis is much greater for ambulatory BP monitoring (ABPM) than daytime officemeasurements. The 2013 ABPM guidelines specified herein are based on ABPM patient outcomes studies and constitute asubstantial revision of current knowledge. The asleep SBP mean and sleep-time relative SBP decline are the most significantpredictors of CVD events, both individually as well as jointly when combined with other ABPM-derived prognostic markers.Thus, they should be preferably used to diagnose hypertension and assess CVD and other associated risks. Progressivedecrease by therapeutic intervention of the asleep BP mean is the most significant predictor of CVD event-free interval. The24-h BP mean is not recommended to diagnose hypertension because it disregards the more valuable clinical informationpertaining to the features of the 24-h BP pattern. Persons with the same 24-h BP mean may display radically different 24-hBP patterns, ranging from extreme-dipper to riser types, representative of markedly different risk states. Classification ofindividuals by comparing office with either the 24-h or awake BP mean as “masked normotensives” (elevated clinic BP butnormal ABPM), which should replace the terms of “isolated office” or “white-coat hypertension”, and “maskedhypertensives” (normal clinic BP but elevated ABPM) is misleading and should be avoided because it disregards the clinicalsignificance of the asleep BP mean. Outcome-based ABPM reference thresholds for men, which in the absence ofcompelling clinical conditions are 135/85 mmHg for the awake and 120/70 mmHg for the asleep SBP/DBP means, are lowerby 10/5 mmHg for SBP/DBP in uncomplicated, low-CVD risk, women and lower by 15/10 mmHg for SBP/DBP in male andfemale high-risk patients, e.g., with diabetes, chronic kidney disease (CKD), and/or past CVD events. In the adult population,

Address Correspondence to Prof. Ramón C. Hermida, Ph.D., Bioengineering and Chronobiology Labs, University of Vigo; Campus Univer-sitario Vigo, 36310 Spain. Ph.: 34-986-812148; Fax: 34-986-812116; E-mail: [email protected]. Francesco Portaluppi, M.D., Ph.D. Hypertension Center, S. Anna Hospital, University of Ferrara; via Savonarola 9, I-44121 Ferrara,Italy. Ph.: 39-0532-236631; Fax: 39-0532-236622; E-mail: [email protected]

Reprint Address: Same as above.

Submitted August 23, 2012, Returned for revision September 24, 2012, Accepted October 1, 2012

Chronobiology International, 30(3): 355–410, (2013)Copyright © Informa Healthcare USA, Inc.ISSN 0742-0528 print/1525-6073 onlineDOI: 10.3109/07420528.2013.750490

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the combined prevalence of masked normotension and masked hypertension is >35%. Moreover, >20% of “normotensive”adults have a non-dipper BP profile and, thus, are at relatively high CVD risk. Clinic BP measurements, even if supplementedwith home self-measurements, are unable to quantify 24-h BP patterning and asleep BP level, resulting in potentialmisclassification of up to 50% of all evaluated adults. ABPM should be viewed as the new gold standard to diagnose truehypertension, accurately assess consequent tissue/organ, maternal/fetal, and CVD risk, and individualize hypertensionchronotherapy. ABPM should be a priority for persons likely to have a blunted nighttime BP decline and elevated CVD risk,i.e., those who are elderly and obese, those with secondary or resistant hypertension, and those diagnosed with diabetes,CKD, metabolic syndrome, and sleep disorders. (Author Correspondence: [email protected] or [email protected]).

Keywords: Clinical guidelines for the application of ambulatory blood pressure monitoring, Ambulatory blood pressuremonitoring, Cardiovascular risk, Sleep-time blood pressure, Masked normotension, Masked hypertension,True hypertension, Hypertension chronotherapy

OUTLINE

1. Introduction.2. 24-h BP patterns determined by ABPM: Diagnosticimplications.3. Analyses and interpretation of ABPM data: Role ofrest-activity cycle.4. Prognostic value of ABPM-derived characteristics.

4.1. Prognostic value of ABPM: Findings and limit-ations of available studies.4.2. Comparative prognostic value of differentABPM-derived characteristics.4.3. Changes in ABPM during follow-up aspredictors of CVD risk.

5. Masked normotension and masked hypertension.6. The “normotensive non-dipper” paradox.7. J-shaped relationship between BP and CVD risk.8. Reference ABPM thresholds for the diagnosis ofhypertension.

8.1. Sex differences in ABPM reference thresholds.8.2. Reference ABPM thresholds in high-risk patients.8.3. Reference ABPM thresholds in pregnancy.

9. Clinical applications of ABPM.9.1. Secondary hypertension.9.2. Resistant hypertension: Diagnostic andtreatment issues.9.3. Elderly patients.9.4. Diabetes.9.5. Obesity and metabolic syndrome.9.6. Chronic kidney disease (CKD).9.7. Obstructive sleep apnea and othersleep disorders.9.8. Pregnancy.9.9. Evaluation of treatment efficacy.

10. ABPM: Practical considerations.10.1. Sampling rate and duration of ABPM.10.2. Time interval between repeated ABPMevaluations10.3. Editing and validation of ABPM.10.4. Requirements for healthcare personnel incharge of ABPM.10.5. Maintenance and utilization of ABPM devices.10.6. Patient instructions.10.7. Schedulingofpatient appointments forABPM.

11. Conclusions.12. ABPM: Summary of recommendations.

1. INTRODUCTION

Blood pressure (BP) exhibits 24-h variation as a conse-quence of both cyclic day-night, or rather rest-activity,alterations in behavior (e.g., daily routine of activities anddiet, mental stress, and posture), environmental phenom-ena (e.g., ambient temperature, noise, etc.), and endogen-ous circadian (∼24-h) rhythms in neural, endocrine,endothelial, and hemodynamic variables (e.g., plasmanoradrenaline and adrenaline [autonomic nervoussystem] and renin, angiotensin, and aldosterone[renin-angiotensin-aldosterone system]) (Baumgart, 1991;Fabbian et al., 2013; Hermida et al., 2007d; Pinotti et al.,2005; Portaluppi & Smolensky, 2007; Portaluppi et al.,1992b, 1994b, 1996, 2012; Sica & Wilson, 2000; Smolenskyet al., 2007, 2012; Trasforini et al., 1991; Varani et al., 1999).Moreover, circadian rhythms in BP and other phenomena,e.g., those affecting blood coagulation, result in prominent24-h patterns of acute cardiovascular disease (CVD)events, such as myocardial infarction, cardiac arrest,sudden cardiac death, plus ischemic and hemorrhagicstroke (Casetta et al., 2002; Cohen et al., 1997; Elliot et al.,1998; Gallerani et al., 1997; Manfredini et al., 1996a,1996b, 1999a, 1999b, 2004, 2013; Muller et al., 1989; Porta-luppi & Hermida, 2007; Portaluppi et al., 1999). BP ismeasured for clinical purposes because the damagecaused to the arterialwalls is directly and continuouslypro-portional to the BP levels maintained over time. Therefore,BP must be maintained as low as possible for as long aspossible, to the extent that it remains compatible with agood quality of life and does not cause undesired sideeffects or complications, to avert target tissue and organdamage and heightened CVD risk. Time awareness isimplicit in any definition of risk, and the CVD risk due toelevated BP is no exception. Hence, to successfullyprevent such risk, one needs to be aware of all significantBP variations over time, from those occurring during the24 h, particularly ones relating to daytime activity andnighttime sleep, to those derived from lifestyle changesand therapeutic intervention.

In spite of the knowledge on 24-h BP variability, con-ventional, typically daytime, clinic BP measurementsmade in the physician’s office continue to be used as thebasis to diagnose hypertension as well as to evaluate treat-ment efficacy and clinical outcome (Chobanian et al.,

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2003;Mancia et al., 2007a; Pickering et al., 2005). However,these conventional time-unspecified single measure-ments have major disadvantages. They are indicative ofthe BP status of only a very brief and small fraction ofthe entire 24-h BP pattern; moreover, suchmeasurementsare often affected by circumstances in the clinic that exertsignificant pressor effect (“white-coat” effect [Pickering,1995; Pickering et al., 1988]), resulting in higher thanactual BP values. Additionally, clinical BP measurementscan be affected by several potential sources of error(Halberg et al., 1990); these include defects in instrumen-tation (lack of proper validation and periodic calibration ofthe measurement devices plus use of inappropriate sizedBP cuffs, e.g., in slim and overweight subjects) and impro-per technique and procedures of measurement by inade-quately trained healthcare personnel, including “digitpreference” that leads to observer round-off of an arbitrarylast digit, usually to 0 or 5 (Patterson, 1984; Sassano et al.,1987; Wilcox, 1961). Moreover, the within-day variabilityof BP, even among healthy individuals, can be so greatthat the identification of hypertension and its propercateg-orization in terms of severity are highly ambiguous whenbased solely on unspecified single time-of-day measure-ments (Hermida, 1999). Finally, unusually high or lowvalues may occur only at certain times during the 24-hspan thatmay not be covered by casual clinic BP sampling,as in the case of nighttime hypertension.

The use of automatic instrumentation for non-inva-sive ambulatory BPmonitoring (ABPM)makes it possibletoday to follow the time course of BP variation around theclock on an individual basis. ABPM constitutes a methodof BP assessment that compensates for most, if not all, ofthe limitations of office BP measurements (Hermida,1999; Parati et al., 1990). ABPM-derived data allowbetter characterization of BP during everyday activitiesand sleep and, most importantly, the findings correlatemore strongly than clinic BP with target organ damage,CVD risk, and long-term patient prognosis (Ayala &Hermida, 2013; Clement et al., 2003; Dolan et al., 2005;Eguchi et al., 2008; Hansen et al., 2007; Hermida &Ayala, 2002, 2004, 2010; Hermida et al., 2011c, 2012a,2012b, 2013b; Minutolo et al., 2011; Perloff et al., 1983;Salles et al., 2008; Staessen et al., 1999; Verdecchiaet al., 1994). Moreover, ABPM is particularly useful notonly for defining in clinical trials the efficacy of hyperten-sion medications (Coats et al., 1996), but also clinicallyfor evaluating individual patients (Waeber & Brunner,1999), especially according to the administration-time(morning versus evening) treatment regimen as a cost-effective means of better preventing CVD events(Hermida, 2007; Hermida & Smolensky, 2004; Hermidaet al., 2005a, 2007a, 2008a, 2010b, 2011a, 2011b, 2011d,2013c; Portaluppi & Hermida, 2007; Portaluppi & Smo-lensky, 2010; Portaluppi et al., 2012; Smolensky et al.,2010, 2012). However, apart from the relatively, partiallyunjustified, higher cost of the currently marketed ABPMinstruments than conventional cuff assessment, patienttolerability to around-the-clock ABPM has been

discussed as a possible limitation, mostly because itmay induce modest disturbance of nighttime sleep(Degaute et al., 1992). Furthermore, concern has beenraised by some (Mochizuki et al., 1998; Musso et al.,1997) about the low individual reproducibility of the cir-cadian BP profile found between repeated 24-h ABPMsperformed on the same patients. Nonetheless, in termsof reproducibility ABPM is markedly superior to clinicBP measurements (Hermida et al., 2000b, 2004a; Jameset al., 1988).

Based on the above considerations, ABPM providesthe needed essential time-aware and sensitive infor-mation for state-of-the-art individualized diagnosticcategorization, treatment efficacy evaluation, and CVDoutcome prediction. The 2013 recommendations pre-sented herein are based upon detailed analyses of thediagnostic, therapeutic, and prognostic applications ofABPM that should be of common usage, with its intrinsictemporal information, as it is for various other clinicaltests, for instance, the well established examples of glo-merular filtration rate (National Kidney Foundation,2002) and oral glucose tolerance test (American DiabetesAssociation, 2012).

2. 24-H BP PATTERNS DETERMINED BY ABPM:DIAGNOSTIC IMPLICATIONS

Predictable changes during the 24 h in environmentaland biological variables give rise to the circadianpattern in systolic BP (SBP), diastolic BP (DBP), andheart rate. In many, but not all, persons with normal BPor uncomplicated essential hypertension, SBP and DBPdecline to lowest levels during nighttime sleep, risewith morning awakening, and attain peak values duringthe initial hours of daytime activity. In so-called normaldippers, the asleep BP mean is lower by 10-20% relativeto the daytime (awake) BP mean. In addition to this pro-found, sleep-related nighttime decline, the typical circa-dian BP pattern exhibits two daytime peaks, the first oneapproximately 3 h after awakening and the second onearound 12 h after awakening, with a small nadir inbetween, in the afternoon (Hermida et al., 2002a). Theextent of the nighttime BP attenuation has been mainlyquantified through the so-called “sleep-time relative BPdecline”, which is defined as the percent decrease inmean BP during nighttime sleep relative to the meanBP during daytime activity, and calculated as(100×[awake BP mean – asleep BP mean]/awake BPmean). Using this percent ratio, subjects have been arbi-trarily classified as dippers or non-dippers (sleep-timerelative BP decline ≥ or <10%, respectively [O’Brienet al., 1988]). More recently, the classification has beenextended by dividing individuals into four groups:extreme-dippers (sleep-time relative BP decline ≥20%),dippers (sleep-time relative BP decline ≥10% but<20%), non-dippers (sleep-time relative BP decline<10%), and inverse-dippers or risers (sleep-time relativeBP decline <0%, indicating asleep BP > awake BP mean).

Guidelines for ambulatory blood pressure monitoring

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Advantages of identifying the rather simple patternthat describes the circadian BP variation come from thefact that departure from the normal dipper profile maybe indicative of overt pathology (Fabbian et al., 2013;Hermida et al., 2007d; Portaluppi & Smolensky, 2007;Portaluppi et al., 2012; Smolensky et al., 2007, 2012).Attenuation of the normal ≥10% sleep-time BP declinetowards the non-dipper or riser BP patterns is, indeed,associated with elevated risk of end-organ injury, particu-larly to the heart (left ventricular hypertrophy, congestiveheart failure, and myocardial infarct), brain (stroke), andkidney (albuminuria and progression to end-stage renalfailure) (Bianchi et al., 1994; Davidson et al., 2006;Hermida et al., 2003e; Shimada & Kario, 1997; Timioet al., 1995). Numerous studies have consistently shownelevated risk of end-organ injury and increased incidenceof fatal and non-fatal CVD events is significantly associ-ated with blunted sleep-time relative BP decline in thegeneral population (Boggia et al., 2007; Brotman et al.,2008; Burr et al., 2008; Dolan et al., 2005; Hermidaet al., 2011c, 2013b; Ingelsson et al., 2006; Kario et al.,2001; Ohkubo et al., 2002; Verdecchia et al., 1994) and,in particular, in high-risk individuals, such as thosewith diabetes (Astrup et al., 2007; Bouhanick et al.,2008; Eguchi et al., 2008; Hermida et al., 2011b, 2012b;Nakano et al., 1998; Sturrock et al., 2000), chronickidney disease (CKD) (Agarwal & Andersen, 2006a,2006b; Hermida et al., 2011d; Liu et al., 2003; Minutoloet al., 2011; Tripepi et al., 2005), and resistant hyperten-sion (Ayala et al., 2013a; Salles et al., 2008).

The static threshold values for conventional clinicSBP/DBP measurements of ≥140/90 mmHg currentlyused to diagnose hypertension (Chobanian et al., 2003;Mancia et al., 2007a; Pickering et al., 2005) do not takeinto account the predictable circadian pattern in SBPand DBP, and nor do they take into account the markedlyincreased CVD risk associated with blunted nighttime BPdecline (non-dipping). When relying on ABPM, allcurrent recommendations for the diagnosis of hyperten-sion continue to focus on earlier published guidelinesthat propose the threshold values of 130/80 mmHg forthe 24-h SBP/DBP means, but which totally disregardthe valuable information relating to the 24-h BP variabil-ity and other endpoints one obtains by performing ABPM(Chobanian et al., 2003; Head et al., 2012; JCS JointWorking Group, 2012; Mallion et al., 2006; Manciaet al., 2007a; Myers et al., 2005; O’Brien et al., 2003;Ogihara et al., 2009; Pickering et al., 2005); some,although not all (Myers et al., 2005), of these guidelinesalso provide separate reference thresholds for thedaytime and nighttime spans, usually 135/85 mmHg forthe awake SBP/DBP means and 120/70 for the asleepSBP/DBPmeans. Alternatively, it has also been suggestedthese static diagnostic thresholds might be replaced by atime-qualified reference limit reflecting the mostly pre-dictable BP variability during the 24 h (Hermida, 1999;Hermida et al., 2001b, 2004d). Time-specified referencelimits can be constructed in different ways; they can be

model-dependent (Fernández & Hermida, 2000) ormodel-independent (Hermida, 1999; Hermida & Fernán-dez, 1996), and they can be computed as prediction(Hermida et al., 1993; Nelson et al., 1983) or tolerance in-tervals (Hermida & Fernández, 1996; Hermida et al.,1997b). When samples from a reference group of subjectsare available, onemay construct a prediction interval thatis expected to include any single future observation fromthe reference population with a specified confidence(Hermida et al., 1993; Nelson et al., 1983). Alternatively,the reference interval may consist of a somewhatbroader tolerance interval that will include at least aspecified proportion of the population with a stated con-fidence (Hermida & Fernández, 1996; Hermida et al.,2001b, 2004d). The latter kind of reference interval,which is commonly used in industry, has been rec-ommended for application to clinical measurements(Hermida, 1999; Hermida & Fernández, 1996).

Once the time-varying threshold, given for instance bythe upper limit of a tolerance interval (Hermida et al.,2004d), is available, the hyperbaric index (HBI), as adeterminant of BP excess (Halberg et al., 1984; Hermidaet al., 1996, 1998, 2000b, 2002d, 2003a, 2004a), can be cal-culated as the total area of any given subject’s BPabove thethreshold during the entire 24-h period (Figure 1). TheHBI, as well as the duration of BP excess (% time ofexcess, defined as the percentage time during the 24 hwhen the BP of the test subject exceeds the upper limit ofthe tolerance interval), can then be used as nonparametric

FIGURE 1. The concept of the hyperbaric index (HBI), defined astotal area during the entire 24-h period of any given subject’s BP(dashed line) above a time-varying threshold (derived fromABPM assessment of a non-hypertensive reference population)shown in the figure as a tolerance interval, i.e., upper and lowerlimits depicted by the two continuous lines. The percentagetime of BP excess (texcess) is defined as the percent time duringthe 24 h when the BP of the test subject exceeds the upper limitof the tolerance interval of the reference population.

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endpoints for the diagnosis of hypertension. This so-calledtolerance-hyperbaric test, whereby the diagnosis of hyper-tension is based on the HBI calculated with reference to atime-specified tolerance limit, has been shown to providehigh reproducibility in the diagnosis of hypertension(Hermida et al., 2000b). Because the conventional assess-ment of hypertension relies on clinic BP values ≥140/90mmHg for SBP/DBP (Chobanian et al., 2003; Manciaet al., 2007a; Pickering et al., 2005), results based on thedetermination of BP excess usually have been expressedas a function of the maximum HBI, defined as themaximum of the three values of HBI determined for SBP,mean arterial BP, andDBP, respectively, for any given indi-vidual (Hermida et al., 1996, 2000b, 2002d, 2003a, 2004a).A HBI ≥ 15mmHg × h indicates suspected hypertensionand a HBI ≥ 50mmHg × h indicates hypertension. Simi-larly, the hypobaric index (HBO), defined as total area ofany given subject’s BP below the lower limit of the toler-ance interval during the entire 24-h period, can bereadily used as a sensitive endpoint for suspicion of poten-tially too-lowBP, especially in treatedhypertensivepatients(Hermida et al., 1996, 2000b).

Advantages of the tolerance-hyperbaric test forthe diagnosis of hypertension include: (i) easy visualinterpretation of the 24-h BP pattern for the tested indi-vidual (Figure 1); (ii) quantitative evaluation of hyperten-sion severity through the value of the HBI; (iii) analysis ofany subject’s BP in terms of his/her rest-activity cycleinstead of meaningless clock time (Section 3); and (iv)diagnosis of hypertension based on time-specified toler-ance limits calculated taking into account factors ofpotential prognostic value in terms of target organinjury and CVD risk assessment, including patient’s ageand sex, and/or concomitant clinical conditions, e.g., dia-betes, CKD, and/or previous CVD events. The availablesoftware containing the tolerance-hyperbaric test,described in detail elsewhere (Hermida et al., 2002d),allows ABPM evaluation in <1 s and it has alreadyproven to be an effective analytical tool when ABPM is

used to evaluate therapeutic interventions for CVD riskreduction (Hermida et al., 2010b, 2011b, 2011c, 2011d,2012b, 2013b, 2013g). As such, it is currently used in pro-spective population outcome studies as the standardapproach for CVD risk assessment plus guide to individ-ualizing hypertension therapy based on ABPM findings(Ayala et al., 2013b; Crespo JJ et al., 2013; Hermidaet al., 2013j; Mojón et al., 2013; Moyá et al., 2013; Ríoset al., 2013), and we recommend it be utilized as afuture standard procedure in the clinic setting.

Limitations of the 24-h BP mean as a diagnosticparameter are illustrated in Figures 2 and 3. The graphon the left of Figure 2 represents the 24-h SBP pattern(dashed thick line) of a normotensive man plotted withrespect to circadian time-specified tolerance limits (con-tinuous thin lines) calculated from the data of a referencepopulation of normotensive individuals (Hermida et al.,2004d), as a function of sex and rest-activity cycle (timeexpressed relative to hours after awakening from night-time sleep). The dark bar on the lower horizontal axisindicates the nighttime sleep span for this man, as deter-mined by wrist actigraphy (Section 3). The graph showsSBP is within the normotensive range as visible in relationto the upper and lower tolerance limits throughout the 24h, corroborating the diagnosis of normotension, as alsoone might infer by using the current guidelines with the24-h SBP mean being 124.5 mmHg. The sleep-time rela-tive SBP decline of 17% indicates he has a normal dipperBP pattern. The graph on the right of Figure 2 representsthe SBP (dashed line) of a different man with an extreme-dipper BP pattern (sleep-time relative SBP decline of24.3%), daytime HBI of 67.5 mmHg X h, quite above thediagnostic threshold for hypertension (Hermida et al.,2000b, 2002d), and too-low nighttime SBP, all documen-tedmarkers of increased CVD risk. The 24-h SBPmean ofthis hypertensive patient, however, is also 124.5 mmHg.

The graph on the left of Figure 3 shows the 24-h SBPpattern of a third man with a sleep-time relative BPdecline of 5.4% (non-dipper), nighttime HBI of

FIGURE 2. 24-h SBP pattern (dashed thick lines) of a normotensive dipper subject (left) and a hypertensive extreme-dipper patient (right),plotted with respect to circadian time-specified tolerance limits (continuous thin lines), calculated from a reference population of normo-tensive individuals as a function of their rest-activity cycle and sex.

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39.5 mmHg X h, and asleep SBP mean of 122.1 mmHg,thus corroborating the diagnosis of hypertension andelevated CVD risk, even though his 24-h SBP mean isalso 124.5 mmHg, below the currently accepted diagnos-tic threshold of hypertension. Finally, the graph on theright of Figure 3 presents the SBP of a fourth man witha riser BP pattern (sleep-time relative SBP decline of-2.4%), associated with the highest CVD risk among allthe possible BP patterns, and nighttime HBI of 77.2mmHg X h. Despite his elevated CVD risk, that is mark-edly greater than all of the other individuals representedin Figures 2 and 3, the 24-h SBP mean is again 124.5mmHg. These illustrative examples indicate the same24-h “normal” BP mean might be associated with totallydifferent circadian BP patterns and, thus,markedly differ-ent CVD risk. Accordingly, the 24-h BP mean is insuffi-cient and therefore not recommended for use in makingthe diagnosis of hypertension and assessing CVD risk.

The mathematical calculation of mean BP values is anadditional relevant issue that is typically omitted in thecurrent guidelines (Chobanian et al., 2003; Head et al.,2012; Mancia et al., 2007; Pickering et al., 2005). This iscrucial, as many diagnostic parameters derived fromABPM, i.e., the awake, asleep, and 24-h mean, and thesleep-time relative BP decline values, are based on esti-mation of mean BP levels, frequently calculated just asthe simple arithmetic average of all the BP values deter-mined by ABPM. However, the arithmetic mean ishighly dependent on sampling rate. Typically, ABPM isperformed by measuring BP at a higher rate duringdaytime activity than nighttime sleep. This leads tomarked overestimation of the true 24-h BP mean innormal dippers (because of the greater number ofmeasurements performed when BP is highest, i.e.,during the awake/activity span) and its potential under-estimation in non-dippers/risers (because BP ismeasured less frequently during the sleep period, eventhough the asleep BP values are atypically high in thesetypes of patients). An easy alternative is to calculate 24

individual means, one for each hourly class, and thenderive the 24-h BP mean as the average of the resulting24 hourly means (Frank et al., 2010; Octavio et al.,2010). This procedure, however, might not be fully validfor calculation of the awake and asleep BP means, as theawake and asleep spans might not necessarily be aninteger numbers of hours. The best alternative is todivide each of the awake and asleep spans into aninteger number of classes of identical time length, calcu-late the mean BP in each class, and average these result-ing means to obtain proper estimation of the awake andasleep BP means. Comparison of these more accuratemean values between individuals or populations wouldadditionally require an estimator of BP variance thatcan be easily obtained following the approach describedby Dixon & Massey (1983).

3. ANALYSES AND INTERPRETATION OF ABPM DATA:ROLE OF REST-ACTIVITY CYCLE

The mechanisms underlying the loss of the normaldecline in BP during sleep that characterizes non-dipping are as yet unclear (Fabbian et al., 2013;Hermida et al., 2007d; Kanbay et al., 2008; Pickering,1990; Portaluppi & Smolensky, 2007; Portaluppi et al.,2012; Smolensky et al., 2007, 2012). The non-dippingpattern has been reported to be frequent in secondary hy-pertensive patients with endocrine abnormalities andautonomic nervous system dysfunction (Hermida et al.,2007d). Some results indicate the abnormal 24-h BP pat-terns are related to circadian dysfunction of the auto-nomic nervous system (Kario et al., 1997; Ragot et al.,1999). Also, enhanced sodium sensitivity has beenshown to be an independent determinant of the dimin-ished nighttime fall of BP in essential hypertension (Uzuet al., 1996), which explains why sodium restriction canrestore the asleep BP decline, especially in those with en-hanced sodium sensitivity (Uzu et al., 1999). It is impor-tant to recognize that non-dipping is highly prevalent in

FIGURE 3. 24-h SBP pattern (dashed thick lines) of a hypertensive non-dipper (left) and a hypertensive riser patient (right), plotted withrespect to circadian time-specified tolerance limits (continuous thin lines), calculated from a reference population of normotensive indi-viduals as a function of their rest-activity cycle and sex.

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adults (Ayala et al., 2013b; Hermida et al., 2013j; Mojónet al., 2013; Ríos et al., 2013) in spite of the fact its sus-pected causes cannot be clinically documented in mostsubjects. Thus, like thewell-established concept of essen-tial hypertension used to categorize patients with primaryBP elevation, one might consider that, under theunknown clinical causes of the blunted asleep BPdecline, a patient with attenuated sleep-time relative BPdecline should be classified and termed as “essentialnon-dipper”.

The availability of noninvasive devices, i.e., actigraphs,to monitor physical activity around the clock has made itpossible to study the effects of changes in daily activity onBP variability. Using this approach, several authors haverelated non-dipping status to increased nocturnal activityand/or abnormalities of sleep (Agarwal & Light, 2010;Blazquez et al., 2012; Huang et al., 2011; Kario et al.,1999; Leary et al., 2000; Mansoor et al., 2000). Theseresults, however, have been mostly based on correlationsbetweenmean values of activity and BP calculated for thedaytime and nighttime spans of normotensive (Karioet al., 1999) or untreated hypertensive patients(Mansoor et al., 2000), without proper evaluation of thepossible relationship between the circadian patterns ofvariation of activity on the one hand and BP on theother hand. Extending previous findings (Hermidaet al., 2002c), the graph on the left of Figure 4 representsthe circadian SBP pattern of 800 hypertensive patients,categorized according to dipping status, who underwentsimultaneous ABPM (cuff on the non-dominant arm)and wrist activity (actigraph on the dominant wrist)for 48 consecutive hours. Asterisks above the lower hori-zontal time axis denote statistically significant differences

between the hourly mean SBP values obtained fordippers and non-dippers as documented by t-tests ad-justed for multiple testing. The information shown inthis figure documents the absence of differencesbetween groups in the awake SBP mean. Despite theexpected differences in the asleep SBP mean derivedfrom the a priori categorization of patients as dipper vs.non-dipper types, the graph on the right of Figure 4 indi-cates similarity of the circadian pattern in wrist activity – awell documented surrogate measure of physical activity.Figure 4 thus indicates the amount of nighttime physicalactivity, alone, does not explain the increase in the asleepBP mean that characterizes non-dipper hypertensivepatients (Hermida et al., 2002c).

Despite the findings documented in Figure 4, one needsto be aware that the 24-h BP pattern is markedly synchro-nizedwith the nighttime rest-daytime activity cycle (Baum-gart, 1991; Fabbian et al., 2013; Hermida et al., 2007d;Portaluppi & Smolensky, 2007; Portaluppi et al., 2012; Smo-lensky et al., 2007, 2012). Thus, the presentation of ABPMfindings in termsof clock time, as so farcustomary, ismean-ingless and should be avoided. To illustrate this point,Figure 5 presents the circadian SBP pattern (dashed thickline) of an apparently healthy man, with the valuesplotted with respect to circadian time-specified tolerancelimits (continuous thin lines) calculated from the data of areference population of normotensive men (Hermidaet al., 2004d), who on average slept 8.9 h and who onaverage went to sleep at 23:58 h. The test subject slept for9 h, from 21:00 to 06:00 h, as corroborated by wrist actigra-phy. In keeping with the most common current approachfor ABPM analysis, the graph on the left of Figure 5 showsthe SBP data of the test subject expressed in reference to

FIGURE 4. 24-h pattern of SBP (left) and wrist activity (right) in dipper and non-dipper patients with grade 1-2 hypertension sampled by48-h ABPM. Each graph shows the hourly means and standard errors of data collected from dippers (continuous line) and non-dippers(dashed line). Dark shading along the lower horizontal axis of graphs denotes the average hours of nighttime sleep across the sample. Non-sinusoidal shaped curves (thick lines) correspond to the best-fitted waveform models determined by population multiple-componentanalysis (Fernández & Hermida, 1998). MESOR (midline estimating statistic of rhythm) is the 24-h average value of the rhythmic functionfitted to the time series data. Amplitude is one-half the difference between the maximum and minimum values of the best-fitted curve.MESOR and amplitude were compared between groups using a specially developed nonparametric statistical test (Fernández et al., 2004).

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the clock time of each of the measurements. Results fromthis improper analysis of the BP data erroneously indicate(bottom table of Figure 5) the test subject is “hypertensive”(asleep SBP >120 mmHg;HBI 39.7 mmHgXh) and a “non-dipper” (sleep-time relative SBPdeclineof 3.5%).Thegraphon the right of Figure 5 shows the exact same BP data of thesame test subject after being re-expressed in terms of hoursfrom bedtime; the reference tolerance limits did notchange, as the zero time (bedtime) was coincident withmidnight, as indicated above. Analysis of the re-ex-pressed/synchronized data correctly indicates the testsubject is normotensive and a normal dipper. Insummary, analysis of ABPM data in terms of the actualclock time of BP sampling canbemisleading, both in popu-lation studies and in individual patient evaluations.

This example demonstrates why proper synchroniza-tion of BP data to the patient’s specific rest-activitycycle, such as hours from bedtime or hours after awaken-ing, is preferable. This means that accurate informationon the rest-activity cycle must be properly collectedfrom patients. Thus, as a minimum requirement, all indi-viduals undergoing ABPM must maintain a diary listingthe time of retiring to bed at night, awakening in themorning, consumption of meals, participation in exercise,and episodes of unusual physical activity,mood/emotionalstates, and other atypical events that might affect BP. Thisindividualized information can be utilized to determinethecommencement and terminationof thedaytimeactivityand nighttime sleep spans to enable accurate derivation ofthe awake and asleep BPmeans of each subject, after refer-ring each individual’s clock time BP values to, e.g., hoursafter awakening from nighttime sleep; plus, it can beutilized to edit the ABPM data, if required.

Alternatively, subjects evaluated by ABPM might alsosimultaneously wear an actigraph on the dominantwrist to record the level of physical activity during BP

measurement. This compact (about half the size of awristwatch) device works as an accelerometer. Althoughwrist actigraphy provides just a limited estimation of thetotal activity level of the patient at any given time duringthe 24 h, the procedure has been shown to accuratelyidentify the onset, offset, and duration of the sleep andawake periods (Cole et al., 1992; Crespo et al., 2012,2013), with results highly correlated with those obtainedfrom polysomnography, even estimation of the numberof apneas in patients with obstructive sleep apnea(Sadeh et al., 1989). When using actigraphs with ABPM,one must take care to ensure that the internal clocks ofthe two devices are synchronized in terms of actualclock time, e.g., through their respective interfacesusing the same computer. In so doing, one needs firstto confirm the internal clock of the computer is correctlyset to the actual clock time. Actigraphy data also can beused to verify the absence/presence of daytime nappingand nighttime awakenings – due to nocturia, apneas,sleep disturbances associated with ABPM, etc. – and toprecisely define the commencement and termination ofthe daytimewake and nighttime sleep spans of each indi-vidual facilitated by the use of dedicated software (Crespoet al., 2012, 2013), so as to accurately calculate therespective SBP and DBP means and other ABPM-derived variables of clinical interest.

4. PROGNOSTIC VALUE OF ABPM-DERIVEDCHARACTERISTICS

4.1. Prognostic Value of ABPM: Findings and Limitations ofAvailable StudiesDuring the past two decades, specific features of theABPM-determined 24-h BP pattern have been assessedas mediators of injury to target tissues and triggers ofand risk factors for CVD events, such as angina pectoris,

FIGURE 5. 24-h SBP pattern (dashed thick lines) of a normotensive dipper man plotted with respect to circadian time-specified tolerancelimits (continuous thin lines) calculated from a reference population of normotensive individuals as a function of rest-activity cycle and sex.The same BP data are represented as a function of clock time (left) and hours from bedtime (right).

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myocardial infarction, cardiac arrest, sudden cardiacdeath, plus ischemic and hemorrhagic stroke. Forinstance, the extent of the BP surge upon awakeninghas been associated with increased CVD morbidity andmortality in some, but not all, studies (Gosse et al.,2004; Israel et al., 2011; Kario et al., 2003; Metoki et al.,2006; Verdecchia et al., 2012). The morning BP surge isusually calculated as the difference between the averageBP during the initial 2 h after wake-up time (i.e., the so-called morning BP) and the hourly BP average centeredon the lowest BP reading recorded during nighttimesleep (i.e., so-called lowest sleep BP).

The findings of prospective studies that investigatedthe prognostic significance of the morning BP surge areinconsistent. In the recently reported MAPEC (Monitori-zación Ambulatoria para Predicción de Eventos Cardio-vasculares, i.e., Ambulatory Blood Pressure Monitoringfor Prediction of Cardiovascular Events) Study (Hermidaet al., 2011c), the authors found a larger morning BPsurge was associated with a significantly lower CVDrisk, in line with the lower risk associated with increaseddipping of the circadian BP pattern (see Section 4.2.). Thehighest risk was, indeed, found in subjects with the riserpattern (asleep BP mean > awake BP mean) and, thus,characterized by a negative morning BP surge, i.e., a BPreduction after awakening from nighttime sleep. Verdec-chia et al. (2012) also reported lowest CVD risk in hyper-tensive patients of the first quartile of the morning BPsurge, fully corroborating the novel conclusions fromthe MAPEC Study (Hermida et al., 2011c). Contrastingfindings have been reported by others: a morning BPsurge within the top decile was associated with higherrisk of stroke in the Jichii Medical School ABPM study(Kario et al., 2003) and of total CVD events in the Bor-deaux hypertensive cohort study (Gosse et al., 2004).These results, however, might be misleading, as analysesof the prognostic value of the morning BP surge were notproperly adjusted by other significant confounders, inparticular, the asleep BP mean. Moreover, results of theJapanese study conducted by Kario et al. (2003) seemto be inconsistent with their reported higher prevalenceof events among patients in the same database with theriser BP pattern (Kario et al., 2001). Finally, themorning BP surge is poorly reproducible, irrespective ofwhether it is analyzed as a continuous or categorical vari-able (Wang et al., 2007; Wizner et al., 2008). In con-clusion, the morning BP surge does not seem to be anindependent marker of CVD risk; an increased morningBP surge might indeed be associated with lower risk ofCVD events (Hermida et al., 2011c; Verdecchia et al,2012), contrary to the most common current belief.

As indicated above, numerous studies have consistentlyshown an association between blunted sleep-time relativeBP decline (non-dipper BP pattern) and increased inci-dence of fatal and non-fatal CVD events (Astrup et al.,2007; Ayala et al., 2013a; Boggia et al., 2007; Brotmanet al., 2008; Burr et al., 2008; Dolan et al., 2005; Eguchiet al., 2008; Hermida et al., 2011b, 2011c, 2011d, 2012b,

2013b; Ingelsson et al., 2006; Kario et al., 2001; Nakanoet al., 1998; Ohkubo et al., 2002; Salles et al., 2008; Sturrocket al., 2000; Verdecchia et al., 1994). Independent prospec-tive studies have also reported the asleep BP mean is abetter predictor of CVD events than the awake or 24-hBP means (Agarwal & Andersen, 2006a, 2006b; Amaret al., 2000; Ayala et al., 2013a; Ben-Dov et al., 2007;Boggia et al., 2007; Bouhanick et al., 2008; Dolan et al.,2005; Fagard et al., 2008; Fan et al., 2010; Hermida et al.,2011c, 2012b, 2013b, 2013e; Kikuya et al., 2005; Minutoloet al., 2011). Limitations of most of these previousstudies are: (i) frequent use of fixed clock hours to definemorning awakening and bedtime at night, such that thedaytime and nighttime BP means were calculatedwithout assessing and taking into account the actual restand activity spans of the individual patients; and (ii) analy-sis of the prognostic value of dipping status and nighttimeBP mean without proper adjustment for the daytimeBP mean.

A major additional limitation of all previous ABPM-based prognostic studies is reliance on only a single base-line profile from each participant at the time of inclusion,without accounting for potential changes in the level andcircadian pattern of ambulatory BP thereafter during thesubsequent years of follow-up, as a consequence of BP-lowering therapy, aging, and/or development of targetorgan damage and concomitant diseases. Thus, resultsof studies so far reported pertaining to the prognosticvalue of ABPM for CVD risk are based on the assumptionthat the features of the 24-h ABPM pattern do not changeover time, i.e., during the years of follow-up. In otherwords, it is assumed that event-subjects with an elevatedsleep-time BP mean at the time of baseline evaluation,many years before the occurrence of the event, continuedto have an elevated sleep-time BPmean during the entirefollow-up span. Furthermore, due to the lack of periodicmultiple evaluations with ABPM in all previouslyreported studies, except the MAPEC one describedbelow (Hermida, 2007; Hermida et al., 2010b, 2011b,2011c, 2011d, 2012a, 2012b, 2013b, 2013e, 2013g), thepotential reduction in CVD risk associated with modifi-cation of the prognostic ABPM parameters, i.e., eitherincrease of the sleep-time relative BP decline towards amore normal dipping pattern or reduction of the asleepBP mean, was not evaluated. Finally, most studiesreported results derived from investigating mainly oneunique ABPM characteristic, e.g., either a BP meanvalue, or BP dipping status, or BP variability, ormorning BP surge, without comparison or appropriateadjustment for the prognostic value of additionalABPM-derived characteristics. Thus, whether or not theprognostic value of ABPM in predicting CVD eventsmay be improved by the combined use of novel sensitiveparameters, such as the sleep-time relative BP decline,morning BP surge (Kario et al., 2003), or the recently pro-posed ambulatory arterial stiffness index (AASI, calcu-lated as 1 minus the regression slope of DBP on SBPfrom ABPM [Dolan et al., 2006]), in conjunction with

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the more traditional mean BP values and/or determi-nants of BP variability, has only recently been elucidated(Hermida et al., 2011c).

4.2. Comparative Prognostic Value of Different ABPM-Derived CharacteristicsThe MAPEC Study was specifically designed to prospec-tively investigate whether specific changes in the circa-dian BP profile alter, i.e., reduce CVD risk (Hermida,2007; Hermida et al., 2010b, 2011b, 2011c, 2011d,2012a, 2012b, 2013b, 2013e, 2013g). Complete details ofthe rationale and design of the study are described in pre-vious publications (Hermida, 2007; Hermida et al.,2010b). In summary, the authors prospectively studied3344 subjects (1718 men/1626 women), 52.6 ± 14.5(mean ± standard deviation [SD]) yrs of age, with thebaseline BP ranging from normotension to sustainedhypertension according to ABPM criteria, during amedian follow-up of 5.6 yrs. Those with hypertension atbaseline were randomized to ingest all their prescribedhypertension medications upon awakening or ≥1 ofthem at bedtime. At baseline, BP was measured at 20-min intervals from 07:00 to 23:00 h and at 30-min inter-vals during the night for 48 h, and physical activity wassimultaneously monitored every minute by wrist actigra-phy to accurately derive the awake and asleep BP means.Identical ABPM assessment was scheduled annually andmore frequently (quarterly) if hypertension treatmentwas adjusted. Just before commencing each 48-h ABPMsession, the same investigator obtained six consecutiveclinic cuff BP measurements after the subject hadrested in a seated position for ≥10 min. Investigatorsblinded to the timed-treatment scheme of the random-ized hypertensive patients reviewed the complete clinicalrecords of all enrolled participants at least annually aswell as the year following their last ABPM for assessmentof CVD morbidity and mortality. Registered eventsincluded: death from all causes, myocardial infarction,angina pectoris, coronary revascularization, heartfailure, acute arterial occlusion of the lower extremities,thrombotic occlusion of the retinal artery, hemorrhagicstroke, ischemic stroke, and transient ischemic attack.

During the median follow-up period of 5.6 yrs (range.5 to 8.6 yrs) in the MAPEC Study, the authors documen-ted 331 events (58 deaths, 45 myocardial infarctions, 51cases of severe angina pectoris, 35 coronary revasculari-zations, 44 cerebrovascular events, 46 heart failures, 21cases of aortoiliac occlusive disease, and 31 thromboticocclusions of the retinal artery). Table 1 (left column)reports the hazard ratio (HR) of total CVD events esti-mated by the Cox proportional-hazard model, calculatedon the basis of the baseline ABPM profile of each partici-pant, and adjusted for patient’s sex and age, and diagno-sis of diabetes, anemia, and CKD. Table 1 (left column)indicates the HR of CVD events, as expected, wasgreater with progressively higher clinic as well as ambu-latory BP (Hermida et al., 2011c, 2013b). For each ofthe three clinical criteria of SBP, DBP, and pulse pressure

(PP, difference between SBP and DBP) derived by thearound-the-clock ABPM, the asleep BP mean was themost significant predictor of CVD outcome among allthe tested BP parameters (Table 1). Interestingly, agreater either morning or pre-awakening BP surge calcu-lated as previously defined by Kario et al. (2003) was sig-nificantly associated with lower, not higher, CVD risk(Table 1, left column). This finding is in agreement withthe highly significant association between increasedsleep-time relative SBP and DBP decline and reducedCVD risk (Table 1); indeed, a significant relationshipbetween normal dipping of the circadian BP patternand event-free survival was verified. The morning BPand the lowest sleep BP, calculated as BP averageswithin short (2- or 1-h) time intervals immediatelyupon awakening or during sleep, respectively, providedpoorer prognostic value than the awake and asleep BPmeans, respectively (Table 1). The adjusted Coxregression model with the asleep SBP mean had thelowest Akaike Information Criterion (AIC) (Akaike,1974) among all the other parameters tested in Table 1.Difference in the AIC with respect to the asleep SBPmean was ≥21 for every other tested parameter, indicat-ing a considerably poorer prognostic model for all theABPM-derived characteristics listed in Table 1 accordingto the rules proposed by Burnham & Anderson (2004).The findings of the analyses based on data of the lastABPM obtained from each participant at his/her finalevaluation were similar, namely, the asleep SBP meanwas the most significant predictor of both total andmajor CVD events – a composite of CVD death, myocar-dial infarction, and stroke (Hermida et al., 2013b).

The authors further evaluated the potential combinedcontribution of the multiple BP parameters listed inTable 1 to CVD risk (Hermida et al., 2011c). Coxregression analyses using the corresponding asleepSBP, DBP, or PP mean as an additional confounder(Table 1, center column) indicated clinic BP was not asignificant predictor of outcome in the models thatalready included the ABPM-derived asleep BP mean. In-terestingly, when the analyses were corrected for theasleep BP mean, an attenuated awake BP mean (for thesame asleep BP mean, an attenuated awake mean indi-cates enhanced non-dipping) was found to be associatedwith higher, not lower, CVD. Since the asleep SBP meanwas the single most significant predictor of CVD risk, theauthors further evaluated the potential contribution toCVD risk by all the clinic and ambulatory BP character-istics when adjusted for the asleep SBP mean (Table 1,right column). The analysis indicated the best joint fullyadjusted model for predicting CVD events includedonly the asleep SBP mean (HR = 1.23, 95% CI [1.16 -1.32], p < .001) and the sleep-time relative SBP decline(HR = .98 [.97 - .99], p = .019). Other variables, includingthe awake and 48-h SBP means, morning surge, SD ofthe awake, asleep, and 48-h time spans, AASI, and allparameters derived from DBP and PP, provided signifi-cantly less prognostic value or were not statistically

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significant at all when the asleep SBP mean was simul-taneously included in the Cox regression models.

To further investigate the clinical impact of the awakeand asleep BP on the risk of CVD events, the authorsdivided the studied population into four groups accord-ing to BP level at the final evaluation, i.e., normal or

elevated, using the thresholds of 135/85 mmHg for theawake SBP/DBP means and of 120/70 mmHg for theasleep SBP/DBP means (Mancia et al., 2007a), indepen-dent of clinic BP (Hermida et al., 2012a, 2013b). Theresults, as depicted in Figure 6, indicate the: (i) adjustedHRs were equivalent in subjects with normal asleep BP,

TABLE 1. Adjusted HR of total CVD events associated with baseline clinic and ambulatory BP

Parameter Adjusted HRFurther adjusted for corresponding

asleep meanFurther adjusted for asleep

SBP mean

SBPClinic 1.15 (1.09 - 1.21) * 1.04 ( .98 - 1.10) 1.04 ( .98 - 1.10)Awake mean 1.19 (1.12 - 1.27) * .93 ( .84 - 1.03) .93 ( .84 - 1.03)Asleep mean 1.25 (1.19 - 1.32) * — —48-h mean 1.23 (1.16 - 1.32) * .87 ( .75 - 1.01) .87 ( .75 - 1.01)Sleep-time relative decline .96 ( .95 - .97) * .98 ( .97 - .99) † .98 ( .97 - .99) †SD, awake 1.07 (1.05 - 1.10) * 1.03 ( .97 - 1.09) 1.03 ( .97 - 1.09)SD, asleep 1.05 (1.02 - 1.08) * 1.01 ( .98 - 1.04) 1.01 ( .98 - 1.04)SD, 48-h 1.06 (1.03 - 1.09) * 1.02 ( .99 - 1.05) 1.02 ( .99 - 1.05)Morning surge .98 ( .97 - .99) * .99 ( .98 - 1.00) ‡ .99 ( .98 - 1.00) ‡Pre-awakening surge .98 ( .97 - .99) * .99 ( .98 - 1.00) .99 ( .98 - 1.00)Nighttime fall .99 ( .98 - .99) † 1.00 ( .99 - 1.01) 1.00 ( .99 - 1.01)Morning BP 1.11 (1.06 - 1.18) * .93 ( .88 - .98) † .93 ( .88 - .98) †Lowest sleep BP 1.22 (1.16 - 1.28) * .90 ( .76 - 1.08) .90 ( .76 - 1.08)

DBPClinic 1.06 (1.01 - 1.11) ‡ 1.00 ( .95 - 1.06) .99 ( .95 - 1.05)Awake mean 1.03 ( .98 - 1.09) .87 ( .80 - .94) † .93 ( .85 - 1.01)Asleep mean 1.12 (1.06 - 1.18) * — .96 ( .90 - 1.02)48-h mean 1.06 (1.01 - 1.12) ‡ .79 ( .70 - .90) * .94 ( .88 - 1.00)Sleep-time relative decline .96 ( .95 - .97) * .97 ( .96 - .98) * .99 ( .98 - .1.00)SD, awake 1.08 (1.03 - 1.13) † 1.06 (1.02 - 1.22) ‡ 1.04 ( .99 - 1.10)SD, asleep 1.02 ( .98 - 1.06) 1.01 ( .98 - 1.06) .99 ( .95 - 1.03)SD, 48-h 1.03 ( .98 - 1.08) 1.03 ( .98 - 1.08) 1.02 ( .98 - 1.07)Morning surge .97 ( .96 - .98) * .97 ( .96 - .99) * .98 ( .97 - .99) †Pre-awakening surge .97 ( .96 - .98) * .98 ( .96 - .88) * .98 ( .97 - .99) ‡Nighttime fall .98 ( .97 - .99) † .98 ( .97 - .99) † .99 ( .98 - 1.01)Morning BP 1.01 ( .97 - 1.05) .91 ( .87 - .95) * .94 ( .90 - .98) †Lowest sleep BP 1.11 (1.06 - 1.17) * 1.11 ( .99 - 1.24) .98 ( .92 - 1.05)

PPClinic 1.10 (1.06 - 1.13) * 1.01 ( .96 - 1.06) 1.03 ( .99 - 1.07)Awake mean 1.13 (1.09 - 1.18) * .95 ( .87 - 1.04) 1.02 ( .96 - 1.08)Asleep mean 1.14 (1.11 - 1.18) * — 1.05 ( .98 - 1.12)48-h mean 1.15 (1.10 - 1.19) * .92 ( .82 - 1.05) 1.02 ( .96 - 1.09)Sleep-time relative decline .98 ( .97 - .99) * .99 ( .98 - 1.00) .99 ( .98 - 1.00)SD, awake 1.11 (1.07 - 1.16) * 1.02 ( .97 - 1.08) 1.03 ( .98 - 1.09)SD, asleep 1.10 (1.06 - 1.15) * 1.04 ( .99 - 1.09) 1.03 ( .98 - 1.08)SD, 48-h 1.13 (1.09 - 1.18) * 1.04 ( .99 - 1.10) 1.05 ( .99 - 1.10)Morning surge .99 ( .98 - 1.00) .99 ( .98 - 1.01) .99 ( .98 - 1.01)Pre-awakening surge .97 ( .96 - .99) * .99 ( .98 - 1.01) .99 ( .98 - 1.00)Nighttime fall .99 ( .98 - 1.01) 1.01 ( .99 - 1.02) 1.00 ( .99 - 1.01)Morning BP 1.09 (1.06 - 1.13) * .95 ( .87 - 1.03) .99 ( .95 - 1.04)Lowest sleep BP 1.11 (1.08 - 1.15) * .93 ( .86 - 1.02) .99 ( .94 - 1.05)AASI 1.02 (1.01 - 1.03) * 1.01 ( .99 - 1.02) 1.01 ( .99 - 1.02)

HRs (95% CI) per each 10 mmHg elevation in SBP, 5 mmHg elevation in DBP and PP, 1% absolute elevation in sleep-time relative BPdecline, 1 mmHg elevation in morning surge, or .01 elevation in ambulatory arterial stiffness index (AASI). Adjustments were applied forsignificant influential characteristics of patient age and sex, and diagnosis of diabetes, anemia, and CKD (left column), with furtheradjustment for the corresponding asleep SBP, DBP, or PP means (center column), or the asleep SBP mean (right column). The sleep-time relative BP decline, index of BP dipping, is defined as the percent decline in BP during nighttime sleep relative to the mean BP duringdaytime activity, and calculated as: (100×[awake BP mean – asleep BP mean]/awake BP mean). SD: standard deviation of BP values.Morning BP surge was calculated as the difference between the average BP during the initial 2 h after wake-up time (i.e., morning BP) andthe hourly BP average centered on the lowest BP reading recorded during nighttime sleep (i.e., lowest sleep BP). Pre-awakening BP surgewas calculated as the difference between the average BP during the initial 2 h after wake-up time and the average BP during the 2 h justbefore wake-up time. Nighttime fall was calculated as the difference between the average BP during the 2 h just before going to bed and thehourly average centered on the lowest BP reading recorded during nighttime sleep. *p < .001, †p < .01, ‡p < .05.

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independent of the awake BP mean; (ii) HRs were equiv-alent between subjects with elevated asleep BP, independ-ent of the awake BPmean; and (iii) subjects with elevatedasleep BP had a significantly higher adjusted HR of CVDevents than those with normal asleep BP, independent ofthe awake BP mean. Results were identical both for totalCVD events (Figure 6, top), and major and more severeCVD events (Figure 6, bottom).

In conclusion, the results of the Cox regression andother statistical analyses corroborate the higher prognos-tic value of CVD events for ABPM than clinic BPmeasure-ments. Among the different individual parametersderived from ABPM (Table 1), the asleep SBP meanwas themost significant predictor of CVD events, both in-dividually and jointly when combined with other ABPM-derived potential prognostic markers in the best possibleCox proportional-hazard model. In fact, only the sleep-time relative SBP decline added significant prognosticvalue to the model that already included the asleep SBPmean and which was corrected for all relevant confound-ing variables. Moreover, when the asleep SBP mean wasadjusted for the awake SBPmean, only the former proved

to be a significant predictor of outcome. CVD risk signifi-cantly increased exponentially when the sleep-time rela-tive SBP decline was <6% and decreased more slightly forsleep-time relative SBP decline values above thisthreshold (Hermida et al., 2013b). These results indicatethe sleep-time relative SBP decline, as a continuous vari-able, and not the dipping classification usually based onan arbitrary 10% threshold value, should be used forappropriate CVD risk assessment.

4.3. Changes in ABPM during Follow-up as Predictors of CVDRiskResults of the time-dependent Cox regression analysis(adjusted for patient’s age and sex, diagnosis of diabetes,anemia, and CKD, baseline BP, and number of hyperten-sion medications) for total CVD events from the MAPECStudy indicated the progressive decrease in the awake,asleep, and 48-h means of SBP, DBP, and PP was associ-ated with significantly increased event-free survival(Hermida et al., 2011c, 2013b). Changes in the BP SD,morning BP surge, and AASI during follow-up wereless, or not at all, significantly associated with reduced/increased CVD risk. Progressive decrease in the asleepBP mean during follow-up was also a significant predic-tor of survival from major CVD events (HR = .81 [.73 -.91] for SBP; HR = .68 [.56 - .82] for DBP; p < .001).When the changes during follow-up in the asleep andawake BP means were entered jointly in the same Coxregression model, decrease in the asleep SBP mean wassignificantly associated with increase in event-free survi-val (adjusted HR per 5 mmHg reduction in the asleepSBP mean being .85 [.79 - .91], p < .001), while thedecrease in the awake SBP was not (HR = 1.00 [.94 -1.05], p = .849). Interestingly, the reduced HR associatedwith each 5 mmHg decrease in the asleep SBP meanduring follow-up was significant for subjects with bothnormal (HR = .81 [.68 - .95]; p = .005) or elevated BP atbaseline (HR = .84 [.79 - .89]; p < .001) (Hermida et al.,2011c).

Considered together, these results not only corrobo-rate that the asleep SBP mean is the most significantprognostic marker of CVD morbidity and mortality, aspreviously suggested by numerous investigators(Agarwal & Andersen, 2006a, 2006b; Amar et al., 2000;Ben-Dov et al., 2007; Boggia et al., 2007; Bouhanicket al., 2008; Dolan et al., 2005; Fagard et al., 2008;Fan et al., 2010; Kikuya et al., 2005; Minutolo et al.,2011), but they also document for the first time thatdecreasing the asleep SBP mean by properly timedhypertension medications significantly reduces CVDrisk. These findings have been fully corroborated inseparate analyses of data derived from the MAPECStudy for patients with diabetes (Hermida et al.,2011b, 2012b), CKD (Hermida et al., 2011d), and resist-ant hypertension (Ayala et al., 2013a). However,changes in clinic SBP and DBP during follow-up werenot significantly associated with either increased or de-creased CVD risk, even when corrected for the

Figure 6. Adjusted HR of total CVD events (top) and major CVDevents (bottom) in the MAPEC Study. Major events included CVDdeath, myocardial infarction, and stroke. Participants were cate-gorized into groups according to the level (normal or elevated)of the ABPM-derived awake and asleep SBP and DBP means.The awake SBP/DBP means were considered normal if <135/85mmHg and elevated otherwise. The asleep SBP/DBP meanswere considered normal if <120/70 mmHg and elevated other-wise. Adjustments were applied for patient sex and age, diagnosisof diabetes or CKD, sleep duration, and hypertension treatmenttime (all medications upon awakening vs. ≥1 medications atbedtime). Updated from Hermida et al. (2012a, 2013b).

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progressive decrease during the 5.6 yrs median follow-up in the asleep SBP mean (Hermida et al., 2011c). Ofrelevance to this finding, Keenan et al. (2009) foundchanges in clinic BP along the course of the PerindoprilAgainst Recurrent Stroke Study (PROGRESS) have lowprobability of yielding reliable information about thetrue changes in BP in response to hypertension medi-cations. Their results prompted the authors to advocatethe urgent need for evidence-based guidelines tomonitor treatment-response and guide clinical practice.Results of the MAPEC Study, awaiting corroborationfrom the ongoing prospective Hygia Project in whichparticipants are also evaluated by periodic 48-h ABPM(Ayala et al., 2013b; Crespo JJ et al., 2013; Hermidaet al., 2013j; Mojón et al., 2013; Moyá et al., 2013;Ríos et al., 2013), indicate ABPM should be considereda requirement to evaluate changes in asleep BP as aprognostic indicator of CVD risk and also its modifi-cation by treatment.

5. MASKED NORMOTENSION AND MASKEDHYPERTENSION

Current guidelines (Chobanian et al., 2003; Mancia et al.,2007a; Pickering et al., 2005) define normotension as aconsistently normal BP and “sustained” hypertensionas a consistently elevated BP based upon both clinicand ambulatory measurements. Discrepancies betweenthe two methods of measurements have been definedas isolated-office or “white-coat” hypertension, i.e., ele-vated clinic BP but normal ambulatory BP, and maskedhypertension, i.e., normal clinic BP but elevated ambula-tory BP (Mancia et al., 2007a). The same guidelines rec-ommend the use of separate threshold values fordaytime and nighttime BP means for the diagnosis of hy-pertension based on ABPM (Chobanian et al., 2003;Mancia et al., 2007a; Pickering et al., 2005). However,classification of subjects into isolated-office andmasked hypertension has most frequently relied, as erro-neously suggested in the guidelines themselves (Manciaet al., 2007a), on the comparison only of daytime clinicand awake-time mean BP values (Angeli et al., 2010;Bobrie et al., 2008; Fagard & Cornelissen, 2007; Gustav-sen et al., 2003; Ohkubo et al., 2005; Pierdomenico &Cuccurullo, 2011; Verdecchia et al., 2005), disregardingentirely the asleep BP mean otherwise used todefine hypertension.

Previous studies have mostly, but not consistently(Gustavsen et al., 2003; Mancia et al., 2006; Verdecchiaet al., 2005), suggested that CVD risk does not differ sig-nificantly between patients who exhibit isolated-officehypertension and those who are normotensive, but it issignificantly higher in masked and sustained hyperten-sion than in normotension (Angeli et al., 2010; Fagard& Cornelissen, 2007; Ohkubo et al., 2005; Pierdomenico& Cuccurullo, 2011). A major limitation of everyone ofthese previous studies is that by classifying subjectsfrom the comparison of clinic and ambulatory awake or

even 24-h BP means (Baguet et al., 2008; Mancia et al.,2006) each of the four resulting categories wouldinclude individuals with either a normal or elevatedasleep BP mean, and thus having a markedly differentCVD risk (Figure 6).

Data from the MAPEC Study allowed prospectiveexamination of the impact of sleep-time BP on the defi-nition of ambulatory hypertension and the associatedprognostic value of isolated-office and masked hyperten-sion, points of disagreement between clinic and ambula-tory BP measurements in the diagnosis of hypertension,i.e., identification of individuals at higher CVD risk(Hermida et al., 2012a). Participants were divided intofour categories – normal BP, isolated-office hypertension,masked hypertension, and sustained hypertension –according to the agreement/disagreement between thediagnosis of hypertension based on clinic and ambula-tory BP measurements using as threshold values 135/85for the awake SBP/DBP means, 120/70 for the asleepSBP/DBP means, and 140/90 for clinic SBP/DBP; theauthors then compared CVD risk between the four cat-egories obtained by defining ambulatory hypertensionon the basis of either the awake BP mean alone, theasleep BP mean alone, or both the awake and asleepBP combined.

Based upon comparison of clinic BP with the awakeBP mean, as done in most previously published studies,there was a non-significant tendency of increasingadjusted HR of total CVD events across the categories(Figure 7, top). The adjusted HR did not differ signifi-cantly between subjects with normal BP, isolated-office,andmasked hypertension. Patients with sustained hyper-tension had a higher HR than those with normal BP(p < .001), but an equivalent HR as those who hadmasked hypertension (p = .545; Figure 7, top). Theresults and conclusions indicating increased HR of CVDevents only in sustained hypertension also were similarwhen analyses were restricted to major CVD events andwhen the 48-h mean in comparison with clinic BP wasused instead of the awake mean for classification(Hermida et al., 2012a).

Participants in the MAPEC Study were also dividedinto the same four categories based upon comparisonof clinic BP with both the ABPM-derived awake andasleep BP means, as a joint unique criterion for defininghypertension versus normotension (Figure 7, bottom).The results indicated: (i) an equivalent adjusted HR ofCVD events (p = .549) between normal BP and isolated-office hypertension; (ii) a non-significantly differentadjusted HR between masked and sustained hyperten-sion (p < .252); and (ii) a highly significant greater HRin masked and sustained hypertension compared toeither normal BP or isolated-office hypertension(p < .001). These differences between groups in the HRof CVD events were slightly greater when classificationwas based on the asleep BP mean alone (Hermidaet al., 2012a).

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The authors further evaluated the risk of CVD eventsin the eight resulting categories of subjects, as shown inTable 2, according to the clinic BP and the ABPM-derived awake and asleep BP means as three different di-agnostic variables. Subjects were classified first into thecategories of normal BP, isolated-office hypertension,masked hypertension, and sustained hypertension bycomparing clinic BP with the awake BP mean alone(columns 1 and 2 in Table 2); then, subjects in each ofthese four categories were further divided in twoclasses according to the agreement/disagreementbetween the awake and asleep BPmean for the diagnosisof hypertension (comparison of columns 2 and 3 inTable 2). The adjusted HR of each group was calculatedin comparison with the reference subjects with normalclinic BP and normal awake and asleep BP means(Group 1). The results can be summarized as follows:

A. Subjects with elevated asleep BP but normal awakeand clinic BP (Group 2) had a significantly greater

adjusted HR (HR = 1.68; p = .034) than subjects withnormal BP in all three BP characteristics (Group 1),but an equivalent HR as those with normal clinic BPwith elevated awake and asleep BP (Group 4; HR =1.77; p = .039 compared to Group 1).

B. Subjects with normal asleep BP, elevated awake BP,and normal clinic BP (commonly classified asmasked hypertension; Group 3) had a comparableHR as the reference group (Group 1) of normotensivesubjects (HR = .71; p = .629).

C. Subjects with elevated asleep BP, normal awake BP,and elevated clinic BP (usually classified as isolated-office hypertension; Group 6) had a significantlygreater HR than the reference group of normotensivesubjects (HR = 2.08; p < .001), but an equivalent HR asthose with elevated BP in all three characteristics(Group 8; HR = 2.36; p < .001 compared to Group 1).

D. Subjects with normal asleep BP but elevated awakeand clinic BP (usually classified as sustained hyper-tension; Group 7) had a HR not significantly differentthan that of Group 1, i.e., the reference group ofnormotensive subjects (HR = .61; p = .348), and fullyequivalent to that of subjects of Group 5 (HR = .87;p = .501), those with elevated clinic BP but normalawake and asleep BP.

Figure 8 presents the adjusted HR of CVD events forthe eight categories described in Table 2. In agreementwith the findings depicted in Figure 5, Figure 8 shows,in terms of CVD risk, that there are mainly two groupsof subjects: (i) a relatively low-risk group composed ofthose with normal asleep SBP/DBP means, and (ii) a sig-nificantly elevated-risk group composed of those withelevated asleep SBP/DBP means, independent of eitherclinic or awake mean BP values.

Apart from the marked difference in CVD risk assess-ment when the asleep BP mean is omitted for classifi-cation in comparison with clinic BP, the findings shownin Table 2 indicate the so far thus reported prevalenceof the four considered categories of patients, i.e.,normal BP, isolated-office hypertension, masked hyper-tension, and sustained hypertension, and thus the realclinical dimension of isolated-office and masked hyper-tension, is surely incorrect. According to the results pre-sented in Table 2: (i) 58.2% of subjects who should belabel masked hypertension based on their elevatedasleep BP (Group 2) were in the past classified as normo-tensive (based on their normal office and ambulatoryawake BP) and thus mistakenly included in the referencegroup to calculate CVD risk of the other categories; (ii)38.2% of subjects with normal office, elevated ambula-tory awake, but normal asleep BP, and thus at low CVDrisk (Group 3), have always been labeled masked hyper-tension; (iii) 12.6% of subjects with elevated office, ele-vated ambulatory awake, but normal asleep BP, in thepast labeled sustained hypertension, should be labeledisolated-office hypertension (Group 7); and (iv) 26.3%of subjects with elevated clinic, normal awake, and

FIGURE 7. Adjusted HR of total CVD events in theMAPEC Study.Adjustments were applied for patient sex and age, diagnosis ofdiabetes or CKD, sleep duration, and hypertension treatmenttime (all medications upon awakening vs. ≥1 medications atbedtime). Subjects were classified into the categories of normalBP, isolated-office hypertension (HT), masked HT, and sustainedHT by comparing clinic BP with either the awake BP mean only(top) or with the awake and asleep BP means used jointly(bottom). Clinic SBP/DBP measurements were considerednormal if <140/90 mmHg and elevated otherwise. The ABPM-derived awake SBP/DBP means were considered normal if <135/85 mmHg and elevated otherwise. The ABPM-derived asleepSBP/DBP means were considered normal if <120/70 mmHg andelevated otherwise. Updated from Hermida et al. (2012a).

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elevated asleep BP (Group 6), in the past labeled iso-lated-office hypertension, should be labeled sustainedhypertension. In conclusion, the asleep BP determinedby ABPM must be used to properly identify out-of-office hypertension and cannot be omitted in the defi-nition of isolated-office and masked hypertension.

Accordingly, these two conditions cannot be defined bycomparing clinic BP with at-home self-measurements,which are not feasible during sleep, as frequently re-ported in the literature and misleadingly recommendedas an alternative to ABPM (Nasothimiou et al., 2012;Parati et al., 2008).

The results presented in Figures 7 and 8 indicate CVDrisk is equivalent in normotension and isolated-office hy-pertension when the asleep SBP/DBP means are prop-erly used for classification, while individuals in thesetwo categories have significantly reduced risk comparedto those with masked and sustained hypertension.Taking these results into consideration, “hypertension”,conceptually connotating a high-risk condition, shouldnot be used when ABPM is normal, regardless of clinicBP values. Accordingly, we recommend the term “iso-lated-office hypertension” be avoided and replaced bythe more appropriate term “masked normotension”.

The recent update of the guidelines for the clinicalmanagement of adult primary hypertension from the Na-tional Institute for Health and Clinical Excellence pro-poses for the very first time the requirement for ABPMto corroborate the diagnosis of hypertension in alladults with elevated clinic BP (National Institute forHealth and Clinical Excellence, 2011). This recommen-dation is mainly based on the potential cost-effectivenessof identifying people with masked normotension so as toavoid unnecessary long-term costly treatment based onclinic BP measurement only (Lovibond et al., 2011).The results summarized in Figures 7 and 8 indicatemasked hypertension represents a relevant andmore sig-nificant clinical burden in terms of increased CVD riskthan masked normotension. Moreover, when properlytaking into account the asleep BP mean for classification,

FIGURE 8. Adjusted HR of total CVD events in the MAPEC Study(Hermida et al., 2012a). Adjustments were applied for patient sexand age, diagnosis of diabetes or CKD, sleep duration, and hyper-tension treatment time (all medications upon awakening vs. ≥1medications at bedtime). Subjects were classified first into the cat-egories of normal BP, isolated-office hypertension (HT), maskedHT, and sustained HT by comparing clinic BP with awake BPmean alone (columns 1 and 2 in Table 2); subjects in each ofthese four categories were further divided in two classes accordingto agreement/disagreement between the awake and asleep BPmean for the diagnosis of hypertension (comparison of columns2 and 3 in Table 2). Clinic SBP/DBP measurements were con-sidered normal if <140/90 mmHg and elevated otherwise. TheABPM-derived awake SBP/DBP means were considered normalif <135/85 mmHg and elevated otherwise. The ABPM-derivedasleep SBP/DBP means were considered normal if <120/70mmHg and elevated otherwise.

TABLE 2. Adjusted HR of total CVD events in subjects classified by comparison of the diagnosis of hypertension based on clinic BP andABPM-derived awake BP mean, asleep BP mean, or both.

ClinicBP

AwakeBP

AsleepBP

Classification byawake BP

Classification byasleep BP

Classification byawake & asleep BP

Group#

Event-rate in %

Adjusted HR [95% CI];p value

Normal Normal Normal N-BP N-BP N-BP 1 4.7 1.00Elevated N-BP M-HT M-HT 2 16.5 1.68 [1.04-2.72]; .034

Elevated Normal M-HT N-BP M-HT 3 2.7 .71 [ .17-2.91]; .629Elevated M-HT M-HT M-HT 4 16.1 1.77 [1.03-3.05]; .039

Elevated Normal Normal ISO-HT ISO-HT ISO-HT 5 5.9 .87 [ .59-1.29]; .501Elevated ISO-HT S-HT S-HT 6 17.6 2.08 [1.33-3.24]; < .001

Elevated Normal S-HT ISO-HT S-HT 7 3.0 .61 [ .22-1.71]; .348Elevated S-HT S-HT S-HT 8 21.0 2.36 [1.68-3.31]; < .001

HR (adjusted by the significant confounding variables of patient sex and age, diagnosis of diabetes and CKD, time of hypertensiontreatment [all medications upon awakening vs. ≥1 at bedtime], and duration of nighttime sleep) was obtained by Cox regressionanalysis using as reference the group of subjects with normal BP according to all three different BP measurements – clinic BP, awakeBP, and asleep BP (Group 1, see text). Clinic SBP/DBP measurements were considered normal if <140/90 mmHg and elevatedotherwise. The ABPM-derived awake SBP/DBP means were considered normal if <135/85 mmHg and elevated otherwise. The ABPM-derived asleep SBP/DBP means were considered normal if <120/70 mmHg and elevated otherwise. In columns 4-6, normal (N-BP) andsustained hypertension (S-HT) are defined as consistently normal BP or elevated BP, respectively, according to both the clinic BP andconsidered ABPM parameter; isolated-office hypertension (ISO-HT) is defined as elevated clinic BP but normal ABPM; maskedhypertension (M-HT) is defined as normal clinic BP but elevated ABPM. Column 8 (event-rate) indicates the percentage of subjectswith a documented event in each of the resulting 8 categories. Updated from Hermida et al. (2012a).

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previous reports have indicated attenuation by about 50%in the prevalence of masked normotension and a signifi-cant two-fold increase in the prevalence of maskedhypertension, mainly in high-risk populations character-ized by a large proportion of patients with the non-dipper/riser BP pattern, i.e., elderly, diabetic, CKD, andresistant hypertension patients (Ayala et al., 2013b;Crespo JJ et al., 2013; Hermida et al., 2013a, 2013j;Mojón et al., 2013; Moyá et al., 2013; Ríos et al., 2013).Accordingly, ABPM must be a requirement for properCVD risk assessment of all individuals, independent ofclinic BP measurements, taking into account the prog-nostic value of the asleep BP mean and sleep-time rela-tive BP decline, two prognostic markers and validatednovel therapeutic targets that can be assessed only byaround-the-clock ABPM.

The differing CVD liability of patients categorized interms of clinic versus ambulatory BPmeasurements indi-cates, from the point of view of the clinical value of ABPMand its applicability to accurately stratify CVD risk, thisdiagnostic technique should not be used for the first-time evaluation of patients already treated with 1 or 2BP-lowering medications. In the absence of a baselineABPM performed before the initiation of treatment,therapy was undoubtedly prescribed in keeping with a di-agnosis based only upon clinic BP measurements. Assuch, ABPM performed for the very first time in treatedpatients is unable to distinguish who, indeed, is hyper-tensive but properly controlled by therapy from thoseprescribed unnecessary therapy because of masked nor-motension. These limitations must be taken into con-sideration when performing first-time ABPM in patientstreated with ≤2 medications who cannot be washed-out, e.g., for about 2 wks before ABPM. In conclusion,in principle first-time evaluation by ABPM should be re-stricted to untreated subjects and patients treated with ≥3BP-lowering medications, those who might thus be trulyresistant to treatment if the awake and/or asleep BPmeans are inadequately controlled (Ayala et al., 2013a;Hermida et al., 2005b, 2008a, 2010c, 2011c, 2013b,2013g, 2013j; Ríos et al., 2013).

6. THE “NORMOTENSIVE NON-DIPPER” PARADOX

As previously discussed, a blunted decline of nighttimeBP (non-dipping) has been associated with poor progno-sis, primarily in patients with sustained hypertension.Nevertheless, studies have shown that normotensiveindividuals with a non-dipper BP pattern may have: (i)increased left ventricular mass and relative wall thicknessand reduced myocardial diastolic function (Hoshideet al., 2003; Soylu et al., 2009); (ii) elevated myocardialrepolarization lability and impaired baroreflex function,suggesting autonomic nervous system dysfunction(Myredal et al., 2010); (iii) increased urinary albuminexcretion (Soylu et al., 2009); (iv) increased prevalenceof diabetic retinopathy (Rodrigues et al., 2010); and (v)impaired glucose tolerance (Li et al., 2008). However, it

is unknown as yet whether the non-dipper BP patternor just elevated BP, alone, is themost important predictorof advanced target organ damage and elevated risk offuture CVD events (Ohkubo et al., 2002).

Hermida et al. (2013e) prospectively investigated therole of dipping status and ambulatory BP level as poten-tial contributing factors to CVD morbidity and mortalityin a recent evaluation of the data obtained from theMAPEC Study. Participants were divided into fourgroups on the basis of the two criteria of dipping statusand ambulatory BP level: (i) dipper versus non-dipper,and (ii) normal ambulatory BP (awake SBP/DBP means<135/85 mmHg and asleep SBP/DBP means <120/70mmHg) versus elevated ambulatory BP. Cox survivalanalyses, adjusted for significant confounding variables,documented that non-dippers experienced significantlyhigher CVD risk than dippers, whether they had normal(p = .017) or elevated ambulatory BP (p < .001). Non-dippers with normal awake and asleep SBP and DBPmeans, who accounted for 21% of the studied population,had a similar HR of CVD events (HR = 1.61 [1.09 - 2.37])as dippers with elevated ambulatory BP (HR = 1.54[1.01 - 2.36]; p = .912 between groups). The results andconclusions were fully equivalent when the authors eval-uated the HR of major CVD events, i.e., a composite ofCVD death, myocardial infarction, and stroke, as well asfor treated and untreated patients analyzed separately(Hermida et al., 2013e).

These novel findings document the risk of CVD eventsis influenced not only by ambulatory BP elevation, butalso by blunted nighttime BP decline, even within thenormotensive range, thus supporting ABPM as a require-ment for appropriate assessment of CVD risk in thegeneral population, as recently advocated (Giles et al.,2012). The elevated CVD risk in “normotensive” individ-uals having a non-dipper BP profile, who might accountfor >20% of the adult population, represents a clearparadox, as those persons have neither “normal BP”nor low CVD risk. This, in turn, indicates the need to re-define the concepts of normotension and hypertension,which have been established on the unique basis of BPlevel, mainly if not exclusively, measured in the clinicduring the daytime and in the absence of knowledge ofthe entire 24-h BP pattern.

7. J-SHAPED RELATIONSHIP BETWEEN BP AND CVDRISK

Several studies have found too great a reduction in clinicBP by hypertension treatment results in increase of CVDrisk, whereas moderate reduction in clinic BP results indecrease of risk (Messerli et al., 2007). Thus, it hasbeen suggested that the relationship between treat-ment-achieved BP and CVD events is J-shaped, decreas-ing as BP is lowered but rising again as BP is furtherdecreased (Boutitie et al., 2002; Irie et al., 1993;Okumura et al., 2005; Voko et al., 1999). This concepthas generated extensive discussion and concern,

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leading to recommendations to lower BP only to a certainlevel (140/90 mmHg for clinic SBP/DBP), even inpatients at high CVD risk, such as those with diabetes(Cushman et al., 2010) or CKD (Appel et al., 2010). Asan example, the Action to Control Cardiovascular Riskin Diabetes (ACCORD) trial failed to demonstrate a differ-ence in the occurrence of CVD events between intensiveand non-intensive treatment goals defined, respectively,in terms of the clinical-cuff SBP targets of <120 and<140 mmHg (Cushman et al., 2010). These results havelead to the question if the currently recommendedtarget goal of clinic SBP/DBP <130/80 mmHg for patientswith diabetes (Mancia et al., 2007a) should be revised(Bangalore et al., 2011; Kendall, 2011). Unfortunately,the ACCORD study did not provide information onABPM, and the time of day of hypertension treatmentwas neither standardized nor reported.

Commonly, the therapeutic strategies used to improveBP control in a hypertensive patient include increase oftherapeutic dose, sequential change of hypertensionmedications, or application of a combination of medi-cations that exert synergic effects (Mancia et al., 2007a).In practice, all such therapeutic strategies typicallyinvolve a common element: the administration of hyper-tensionmedication(s) in themorning – either at the com-mencement of the diurnal activity span or, morecommonly, with breakfast. It is important to realizethat: (i) most marketed medications do not providehomogeneous long-lasting efficacy throughout theentire 24 h, and (ii) no marketed hypertension medi-cation induces greater reduction of the asleep thanawake BP when administered in the morning (Hermida& Smolensky, 2004; Hermida et al., 2005a, 2007a,2011a, 2013c; Portaluppi & Smolensky, 2010; Portaluppiet al., 2012; Smolensky & Portaluppi, 1999; Smolenskyet al., 2010, 2012). Typically, progressive increase in thenumber of BP-lowering medications administered inthe morning results in greater reduction of the awakethan the asleep SBP and DBP means, the result being de-crease in the sleep-time relative BP decline. This is unde-sirable since it is known that progressive reduction ofsleep-time relative BP decline towards a more non-dipper BP pattern (Hermida et al., 2008a) leads to pro-gressively increased CVD risk (Ayala et al., 2013a;Hermida et al., 2010b, 2011c, 2012b, 2013b).

Hermida et al. (2013h) examined, using the data fromthe prospective MAPEC Study, the questions of whetherthe documented J-shaped relationship between clinicBP and CVD risk also applies to ambulatory BP andwhether such a relationship is dependent on the time-of-day regimen of hypertension treatment. Participantsof each of the two randomized treatment-time groups,i.e., all BP-lowering medications scheduled upon awak-ening or ≥1 medications scheduled at bedtime, werefurther divided into quintiles of achieved BP, with theclass having the lowest rate of events used as referencefor each tested BP characteristic, namely clinic BP,awake BP, and asleep BP. The relationship between

achieved clinic SBP and adjusted CVD risk wasU-shaped for the patients randomized to the morning-treatment group; CVD risk was significantly higher(p always < .008) in the first two and the last two quintilescompared with the third quintile (achieved clinic SBPranging between 140 and 150 mmHg). The shape of therelationship between clinic SBP and CVD risk, however,was markedly different for the patients randomized tothe bedtime–treatment group; CVD risk was significantlyhigher (HR = 3.09 [1.33 - 7.18]; p < .001) in the last (i.e.,highest clinic SBP) compared to the first quintile, andthe adjusted HR of CVD events was progressively, butnot significantly, diminished with decreased achievedclinic SBP <160 mmHg. These results on the influenceof time-of-day (i.e., circadian time) of treatment regard-ing the relationship between achieved BP and CVD riskwere similar for clinic DBP and also for the ABPM-derived awake SBP and DBP means (Hermida et al.,2013h).

The relationship between CVD risk and the achievedasleep SBP mean assessed by around-the-clock ABPMdiffered markedly from that described for office BP,being exponential independent of the treatment-timeregimen; CVD risk was lowest in the first quintile(achieved asleep SBP <103 mmHg), and significantlyhigher when the asleep SBP was >115 mmHg. Con-clusions were similar for the achieved DBP mean; CVDrisk was significantly higher when the asleep DBP meanwas >73 mmHg, again independent of treatment-timeregimen. There was no single registered major CVDevent in patients of either treatment-time group with anachieved asleep BP mean <103 mmHg, which rep-resented 22% of the studied population. The absence ofa J-shaped relationship between CVD risk and progress-ive reduction in the asleep SBPmeanwas also document-ed in separate analyses of data from patients with eitheruntreated hypertension or resistant hypertension at base-line (Hermida et al., 2013h).

In conclusion, the proposed J-shaped relationshipbetween achieved BP level and CVD risk, described sofar only on the basis of clinic cuff BP values in patientspresumably treated with hypertension medications inthe morning (Appel et al., 2010; Bangalore et al., 2010;Cushman et al., 2010; Okumura et al., 2005; TRANSCENDInvestigators, 2008; Voko et al., 1999; Yusuf et al., 2008),does not apply to the ABPM-determined asleep BPmean, a more significant and sensitive predictor ofCVD morbidity and mortality than either the daytimeclinic BP or ambulatory awake BP mean (Agarwal &Andersen, 2006a, 2006b; Amar et al., 2000; Ayala et al.,2013a; Ben-Dov et al., 2007; Boggia et al., 2007; Bouha-nick et al., 2008; Dolan et al., 2005; Fagard et al., 2008;Fan et al., 2010; Hermida et al., 2003e, 2011c, 2012b,2013b, 2013e; Kikuya et al., 2005; Minutolo et al., 2011).Accordingly, the J-curve seems to be a manifestation ofthe over-treatment in the morning of elevated BP toachieve the misleading therapeutic goal of progressivereduction in the daytime clinic BP level and disregard

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entirely of the control of asleep BP. The decreased CVDrisk associated with progressive reduction in the asleepSBP mean, more feasible by a bedtime than morninghypertension–treatment regimen (Hermida & Ayala,2009; Hermida & Smolensky, 2004; Hermida et al.,2003d, 2004c, 2005a, 2007a, 2007b, 2007e, 2008b,2009a, 2010a, 2011a, 2013c; Portaluppi & Smolensky,2010; Portaluppi et al., 2012; Smolensky & Portaluppi,1999; Smolensky et al., 2010, 2012), indicates the impor-tance of the proper timing during the 24 h of hyperten-sion medications, in conjunction with the applicationof ABPM for the appropriate assessment of awake andasleep BP control, as an improved and cost-effectivemeans of reducing CVD morbidity and mortality.

8. REFERENCE ABPM THRESHOLDS FOR THEDIAGNOSIS OF HYPERTENSION

Despite the knowledge of the progressive relationshipbetween increase of BP and escalation of CVD risk thatmakes the diagnosis of hypertension based on fixed BPcutoff values rather arbitrary, international guidelinesrecommend the diagnostic threshold of ≥140/90 mmHgfor clinic SBP/DBP in the absence of compelling clinicalconditions (uncomplicated persons), and the lowerthreshold of ≥130/80 mmHg as a therapeutic goal whenpresent, i.e., diabetes, CKD, or past CVD events (Choba-nian et al., 2003; Mancia et al., 2007a; Pickering et al.,2005). Since ambulatory BP values are usually severalmmHg lower than clinic ones, the same guidelinesprovide different thresholds for the diagnosis of hyper-tension based on ABPM, namely an awake SBP/DBPmean ≥135/85 mmHg, or an asleep SBP/DBP mean≥120/70 mmHg (Mancia et al., 2007a). However, differ-ent ABPM thresholds have not yet been recommendedfor uncomplicated lower-risk versus higher-risk persons,as some guidelines indirectly recommend on the basisof clinic BP.

Most published reports have proposed ABPM diag-nostic limits based on either the distribution of ambula-tory BP in reference normotensive populations (Hansenet al., 2008) or the regression of ambulatory BP valueson clinic BP measurements (Bur et al., 2002; Headet al., 2010). A few studies have proposed ABPM diagnos-tic cutoff threshold values based on actual associatedCVD outcomes (Kikuya et al., 2007; Ohkubo et al.,1998), but without differentiating patients according todocumented factors that significantly affect BP regu-lation, such as patient’s sex, and diagnosis of diabetesand CKD, among others (Fabbian et al., 2013; Hermidaet al., 2002a, 2007d; Portaluppi & Smolensky, 2007; Porta-luppi et al., 1990, 2012)

8.1. Sex Differences in ABPM Reference ThresholdsEpidemiologic studies have reported sex differences inBP and heart rate (Ben-Dov et al., 2008; Burt et al.,1995; Hermida, 1999; Hermida et al., 2002a, 2002d,2004d; Kagan et al., 2007; Pimenta, 2012; Reckelhoff,

2001; Roger et al., 2011; Vriz et al., 1997). As shown inFigure 9, typically, men exhibit lower heart rate andhigher BP than women, the differences being larger forSBP than DBP (Hermida et al., 2002a). These differencesfirst become apparent during adolescence and remainsignificant until 55-60 yrs of age (Meininger et al., 2004;Palatini et al., 2001; Pimenta, 2012; Wang et al., 2006).The most recent U.S. National Health and NutritionExamination Survey involving daytime cuff measure-ments confirmed SBP increases progressively with agein both men and women, and also that SBP is higher inmen commencing in early adulthood (Roger et al.,2011). In contrast, the survey found the age-related rateof rise in SBP is steeper for women, such that SBP inwomen is higher than in men during and after the 7th

decade of life. In the overall population, DBP increasesprogressively in both men and women until approxi-mately the 6th decade of life, after which it decreases pro-gressively, men having a slightly higher DBP than womenat all ages. The prevalence and severity of hypertension inwomen increase markedly with advancing age, such thata higher percentage of women thanmen experience highBP after 65 yrs of age (Ong et al., 2008; Roger et al., 2011).Furthermore, BP control is more difficult to achieve inolder women (Lloyd-Jones et al., 2005). Sex-relateddifferences in BP regulation may play a role in the docu-mented male-female dissimilarities in the pathophysiol-ogy of hypertension, treatment responses to medications,tissue and organ damage, and CVD risk (Atalar et al.,2010; Ayala & Hermida, 2010; Burt et al., 1995; Guet al., 2008; Keyhani et al., 2008; Klungel et al., 1998; Liet al., 2006; Manfredini et al., 2011; Ong et al., 2008;Pimenta, 2012; Roger et al., 2011; Safar et al., 2002; Vrizet al., 1997; White et al., 2001; Yoshida et al., 2010).

Hermida et al. (2013i) evaluated the adjusted HR ofCVD events for the participants of the MAPEC Studycategorized by sex and their ABPM-derived awake andasleep SBP/DBP means. The analyses: (i) documentedthe expected increase in the adjusted HR of CVD eventsassociated with progressively elevated ambulatoryawake and asleep SBP/DBP means; (ii) revealed a signifi-cantly greater slope of increasing risk in women com-pared to men with progressively elevated SBP/DBP; and(iii) showed progressively and significantly greater differ-ences in the adjusted HR of total CVD events betweenmen and women for awake SBP/DBP means ≥125/75mmHg and asleep SBP/DBPmeans ≥110/70 mmHg. Fur-thermore, Cox regression analyses indicated significantinteraction between sex of patient and both the awakeand asleep SBP means (p always < .009 [Hermida et al.,2013i]).

Using the baseline ABPM values of CVD event andnon-event male participants of the MAPEC Studyrevealed the maximum combined sensitivity and speci-ficity for the diagnosis of hypertension corresponded tothe proposed outcome (CVD event)-based thresholdvalues shown in Table 3, i.e., 135/85 mmHg for theawake and 120/70 for the asleep SBP/DBP means

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(Hermida et al., 2013i). These findings, based on docu-mented CVD events of the study, are in agreement withthe currently recommended ABPM reference values forthe diagnosis of hypertension in uncomplicatedpersons (Mancia et al., 2007a). However, Cox pro-portional-hazard regression analyses indicated thatwomen attained an equivalent HR of total CVD eventsat much lower BP levels than men, specifically 11.2/6.4mmHg lower for their awake SBP/DBP means and 10.8/6.0 mmHg lower for their asleep SBP/DBP means.Thus, the CVD outcome-based ABPM referencethresholds in women, equivalent to the cutoff values pro-vided in Table 3 for men, are 123.8/78.6 mmHg for theawake and 109.2/64.0 mmHg for the asleep SBP/DBPmeans. Rounding these point estimates to the nearestinteger value ending in 0 or 5 provides the newly pro-posed outcome-based threshold values for women, i.e.,125/80 mmHg for the awake and 110/65 for the asleepSBP/DBP means (Hermida et al., 2013i).

Alternatively, the diagnosis of hypertension might bebased on the tolerance-hyperbaric test, as extensively de-scribed in Section 2. Figure 10 shows the tolerance inter-vals for SBP (top) and DBP (bottom) derived to include90% of the reference population of normotensive individ-uals with 90% confidence (Hermida et al., 2004d). Toler-ance intervals for SBP and DBP were obtained from datasampled by 48-h ABPM in a reference population of 743clinically healthy individuals (400 men and 343 women)and calculated using the mathematical non-parametricmethod described in detail elsewhere (Hermida &Fernández, 1996). These time-specified referencethresholds, expressed in hours after awakening fromnighttime sleep, reflect the circadian BP variability andthe documented sex differences in BP regulation. Inkeeping with previous findings (Hermida et al., 2000b,2002d), hypertension is defined as a HBI ≥50 mmHg Xh, while a HBI ≥15 mmHg X h is indicative of suspectedhypertension that will require repeated subject

FIGURE 9. 24-h pattern of SBP (left) and heart rate (right) of normotensive men (continuous line) and women (dashed line) sampled by48-h ABPM. Each graph shows the hourly means and standard errors of data derived from subjects of each group. Dark shading along thelower horizontal axis of graphs denotes the average hours of nighttime sleep across the sample. Nonsinusoidal shaped curves correspond tothe best-fitted waveform models derived by population-multiple-component analysis (Fernández & Hermida, 1998). MESOR (midline es-timating statistic of rhythm) is the 24-h average value of the rhythmic function fitted to the time series data. Amplitude is one-half the differ-ence between the maximum and minimum values of the best-fitted curve. MESOR and amplitude were compared between groups using aspecially developed nonparametric statistical test (Fernández et al., 2004). Updated from Hermida et al. (2002a).

TABLE 3. Diagnostic threshold values for ABPM in mmHg based on CVD outcome.

ABPM characteristic Men Women High-risk patients

Awake meanSBP 135 125 120DBP 85 80 75

Asleep meanSBP 120 110 105DBP 70 65 60

High-risk patients include those diagnosed with diabetes, CKD, and having experienced a previous CVD event.Alternatively, hypertension might be defined as a hyperbaric index (HBI) ≥50 mmHg X h. The HBI is defined as the total area during theentire 24-h period of any given subject’s BP being above a time-varying threshold defined by a tolerance interval calculated as a function ofpatient sex and CVD risk. A HBI ≥15 mmHg X h indicates suspected hypertension that will require repeated subject evaluation by ABPM toconfirm/refute the diagnosis of hypertension.

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evaluation by ABPM to confirm/refute the diagnosis ofhypertension. Similarly, a HBO (area of BP deficitbelow the lower tolerance limit) ≥50 mmHg X h hasbeen previously utilized to down-titrate therapy intreated hypertensive patients (Hermida et al., 2010b).

8.2. Reference ABPM Thresholds in High-Risk PatientsAs indicated above, different ABPM thresholds have notbeen yet recommended for uncomplicated lower-riskversus higher-risk persons, e.g., patients with diabetes,CKD, and/or past CVD events. Diabetes is among thedocumented factors that significantly affects BP regu-lation and CVD risk (Ayala et al., 2013b; Equiluz-Brucket al., 1996; Fogari et al., 1993; Hermida et al., 2007d; Por-taluppi & Smolensky, 2007; Portaluppi et al., 2012; Rutteret al., 2000). The blunted sleep-time BP decline that ischaracteristic of the non-dipping pattern is also verycommon in patients with CKD (Agarwal & Andersen,2005; Agarwal et al., 2009; Crespo JJ et al., 2013; Davidsonet al., 2006; Mojón et al., 2013; Pogue et al., 2009; Porta-luppi et al., 1990).

Hermida et al. (2013f) evaluated the adjusted HR ofCVD events for the participants of the MAPEC Studycategorized by the presence/absence of diabetes andtheir ABPM-derived awake and asleep SBP/DBP means.

The analyses revealed a significantly greater slope of in-creasing risk with progressively elevated SBP and DBPin patients with than without diabetes, and also showedprogressively and significantly greater differences in theadjusted HR of total CVD events between patients withand without diabetes for awake SBP/DBP means ≥130/75 mmHg and asleep SBP/DBP means ≥110/65 mmHg.Furthermore, Cox regression analyses indicated signifi-cant interaction between diabetes and both the awakeand asleep SBP/DBP means for patients displayingvalues above these thresholds (p always < .023). Accord-ingly, contrary to the conclusions of a recent report bySehestedt et al. (2011), these data document the synergicrelationship with CVD risk between diabetes and increas-ing BP above these thresholds (Hermida et al., 2013f).

Cox proportional-hazard regression analyses furtherindicated that patients with diabetes reached an equiva-lent HR of total CVD events at a lower BP level than thosewithout diabetes, i.e., when the awake SBP/DBP meanwas lower by 14.4/11.3 mmHg, and the asleep SBP/DBP mean was lower by 14.0/7.9 mmHg (Hermidaet al., 2013f). Thus, after rounding the values to thenearest integer ending in 0 or 5, the outcome-basedABPM reference thresholds in patients with diabetes —equivalent to the cutoff values of 135/85 mmHg for theawake and 120/70 for the asleep SBP/DBP means forpatients without diabetes — are 120/75 mmHg for theawake and 105/60 for the asleep SBP/DBP means,which also may be applied to other high-risk groups, asindicated in Table 3.

These ABPM thresholds are slightly lower than thoseof a recent report by Cardoso et al. (2012) stating 125/75 mmHg for the daytime and 110/65 mmHg for thenighttime SBP/DBP means as optimal for patients withdiabetes. These later thresholds, however, derived frompatients with diabetes under hypertension treatment,were calculated in relation to the likelihood of developingmicrovascular complications, rather than upon actualCVD events; in addition, these thresholds were offeredwithout comparison to corresponding ones for patientswithout diabetes. Head et al. (2012) also proposedlower ABPM-threshold values for patients with diabetes,CKD, proteinuria, or previous CVD events, than for un-complicated persons. The ABPM thresholds provided inTable 3 are slightly lower than those suggested by Headet al. (2012) for patients with diabetes, but similar tothose proposed by these authors for hypertensivepatients with proteinuria, although their cutoff valuesare based on regression analyses of ambulatory onclinic BP measurements as opposed to actual CVD out-comes. In conclusion, outcome-based referencethresholds for the diagnosis of hypertension arereduced by 15/10 mmHg for ambulatory SBP/DBP inhigh-risk patients, mainly those with diabetes and CKD.

8.3. Reference ABPM Thresholds in PregnancyConventional clinic BP readings are neither diagnosticnor sufficiently predictive of the development of

FIGURE 10. Sex- and time-specified 24-h 90% tolerance intervalsfor SBP (top) and DBP (bottom) derived from a reference popu-lation of normotensive men and women who were assessed by48-h ABPM, for use in making the diagnosis of hypertension (BPabove the upper tolerance limit) and/or hypotension (BP belowthe lower tolerance limit). Updated from Hermida et al. (2004d).

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hypertension in pregnancy (Hermida & Ayala, 1997,2002, 2004; Hermida et al., 1998, 2003a, 2004c; Peeket al., 1996). The reported sensitivity and specificity ofclinic BP measurements vary greatly between studies,with the sensitivity being as low as 9% (Ayala et al.,1997a) and the positive predictive value being as low as8% (Page & Christianson, 1976). Nonetheless, the diag-nosis of gestational hypertension still relies on conven-tional clinic BP measurements and constant thresholdvalues, i.e., 140/90 mmHg for SBP/DBP after 20 wks ofgestation in a previously normotensive woman (Brownet al., 2001c; Davey & MacGillivray, 1988; Lindheimeret al., 2008).

Many previous studies that have evaluated ABPM forthe diagnosis of hypertension in pregnancy (Bellomoet al., 1999; Brown et al., 1998, 2001a, 2001b; Fergusonet al., 1994; Halligan et al., 1993; Hermida & Ayala,1997, 2005a; Higgins et al., 1997; Kyle et al., 1993; Margu-lies et al., 1987; Penny et al., 1998; for an extensive reviewsee Ayala & Hermida, 2013) have found differentthreshold reference values that only occasionally havebeen tested prospectively (Bellomo et al., 1999;Hermida & Ayala, 2005a). Moreover, there is still con-siderable controversy regarding the comparative prog-nostic value of the awake and asleep BP means forprediction of complications in pregnancy (Brown et al.,2001a, 2001b; Halligan et al., 1993; Kyle et al., 1993).

Hermida & Ayala (1997) performed a study on 113pregnant women sampled for 48 h every 4 wks from thefirst obstetric examination until delivery, thus providing759 ABPM profiles in total. The purpose of this investi-gation was to assess the sensitivity and specificity of the48-h BP mean per trimester of pregnancy in identifyinghypertensive complications in pregnancy. This wasaccomplished by comparing distributions of the 48-hBP mean values of both healthy and complicated preg-nancies, without assuming an a priori threshold for thediagnosis of gestational hypertension based on meanBP. Sensitivity ranged from 32% for DBP in the second tri-mester to 84% for SBP in the third trimester. Specificity,however, was as low as 7% for DBP in the first trimester.Results of this study revealed the threshold values thatwould eventually provide the highest combined sensi-tivity and specificity for the diagnosis of hypertension

in pregnancy are: 111/66 mmHg for the 48-h SBP/DBPmeans during the first trimester of pregnancy, 110/65mmHg during the second trimester, and 114/69 mmHgduring the third trimester. The corresponding thresholdvalues for each of the three trimesters of pregnancywere 115/70, 115/69, and 118/72 mmHg for the awakeSBP/DBP means; and 99/58, 98/56, and 104/60 mmHgfor the asleep SBP/DBP means (Table 4 [Hermida &Ayala, 1997]). These apparently low values, reflectingthe predictable changes in BP during gestation in normo-tensive pregnant women (Ayala & Hermida, 1997b;Hermida et al., 2001a) plus the expected diminished BPin pregnant as compared to non-pregnant women(Ayala & Hermida, 2013; Hermida & Ayala, 2004;Hermida et al., 2001b, 2003a, 2004a), are fully equivalentto those proposed by other independent investigators(Halligan et al., 1993; O’Brien et al., 2003) to definenormal ABPM values in pregnancy.

In the attempt to validate prospectively thesethreshold reference limits, Hermida & Ayala (2005a) cal-culated the sensitivity and specificity of the 48-h, awake,and asleep BPmeans for the early identification of hyper-tension in pregnancy in a study involving 403 (207 nulli-parous) untreated pregnant women. Among them, 235remained normotensive, 128 developed gestationalhypertension, and 40 developed preeclampsia. Thewomen were evaluated by 48-h ABPM at the time ofrecruitment (usually within the first trimester of preg-nancy), and then every 4 wks thereafter until delivery,representing in total 2430 ABPM profiles. The use ofestablished thresholds tested prospectively revealed rela-tively small overlap between healthy and complicatedpregnant women. Only 40 out of the 546 (7.3%) BP pro-files representative of normotensive pregnant women inthe second trimester of gestation showed a 48-h SBPmean >110 mmHg, while 362 out of the 412 (87.9%) pro-files representative of those who later developed gesta-tional hypertension or preeclampsia showed a 48-h SBPmean above this threshold. Results were similar for theawake SBP mean, although the overlap between the dis-tributions of values of normotensive and hypertensivewomen was slightly greater for the asleep SBP mean.The results further indicated a slightly larger overlap ofBP mean values between these two groups during the

TABLE 4. Diagnostic threshold values for ABPM in mmHg for pregnant women as a function of gestational age

ABPM characteristic 1st trimester (<14 wks gestation) 2nd trimester (14-27 wks gestation) 3rd trimester (≥27 wks gestation)

Awake meanSBP 115 115 118DBP 70 69 72

Asleep meanSBP 99 98 104DBP 58 56 60

Alternatively, hypertension in pregnancy might be defined as a hyperbaric index (HBI) ≥15 mmHg X h independent of pregnancy stage.The HBI is defined as the total area during the entire 24-h period of any given pregnant woman’s BP above a time-varying threshold definedby a tolerance interval calculated as a function of gestational age and derived from a reference population of normotensive pregnantwomen.

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first trimester, and a slightly smaller overlap of the datasampled during the third trimester. Thus, the sensitivityand specificity in the diagnosis of hypertension in preg-nancy based on mean SBP values increased with gesta-tional age. For the threshold values provided above(Table 4), at all stages of pregnancy the sensitivity andspecificity of the DBP means were consistently lowerthan they were for the SBP means (Hermida & Ayala,2005a).

Some studies based solely on conventional office BPmeasurements concluded that both maternal age andparity exert significant effects on BP during pregnancy(Christianson, 1976; Ness et al., 1993). These findings,however, are controversial due to the lack of correlationbetween parity and BP shown in other investigations(Lee-Feldstein et al., 1980; Moutquin et al., 1982; Okono-fua et al., 1992). Most important, data obtained from sys-tematic ABPM studies of normotensive pregnant womenhave indicated lack of differences in BP according toparity (Ayala & Hermida, 2001; Hermida & Ayala,2005b; Hermida et al., 2004b). Accordingly, the ABPMthreshold values proposed in Table 4 can be used forthe early identification of hypertension in pregnancy,independent of maternal age and parity.

The sensitivity and specificity ofmeanBP values for theearly identification of hypertension in pregnancy can beimproved by the use of other indexes also derived fromABPM. In particular, the tolerance-hyperbaric test rep-resents a reproducible, noninvasive, and highly sensitivetest for the early identification of subsequent hyperten-sion in pregnancy, including preeclampsia (Hermida &Ayala, 2002; Hermida et al., 1998, 2003a, 2004a).Figure 11 shows the tolerance intervals for SBP (top)andDBP (bottom) derived to include 90%of the referencepopulation of normotensive individuals with 90% confi-dence. These tolerance intervals were obtained, first,from data sampled by 48-h ABPM during the second tri-mester of pregnancy in the reference group of 235 normo-tensive pregnant women referred to above and, second,from a reference population of 504 non-pregnant normo-tensivewomenmatched by age and, to the greatest extentpossible, other clinical characteristics (Ayala & Hermida,2013). For both groups of pregnant and non-pregnantnormotensive women, the graphs in Figure 11 representthe upper and lower limits of the tolerance interval withreference to time during the 24 h, defined in terms ofhours after awakening from nighttime sleep. The upperlimit of the tolerance interval for both groups of womenis not only markedly <140/90 mmHg with reference tooffice values, but also below the ABPM thresholds of135/85 mmHg currently recommended for the diagnosisof essential hypertension in both women and men basedon the awake SBP/DBP means (Chobanian et al., 2003;Mancia et al., 2007a; Pickering et al., 2005). Moreover,the values for the upper and lower limits of the toleranceintervals represented in Figure 11 for pregnant womensampled in their second trimester of gestation are mark-edly lower than those obtained for clinically healthy

normotensive non-pregnant women also studied by48-h ABPM. These time-specified threshold valuesreflect the expected lower SBP and DBP in normotensivepregnant women compared to non-pregnant women(Ayala & Hermida, 2013; Hermida & Ayala, 2004;Hermida et al., 2001b, 2003a, 2004a) as well as the circa-dian pattern of BP variability previously demonstratedin normotensive pregnant women during each trimesterof gestation (Ayala et al., 1997a; Benedetto et al., 1996;Hermida et al., 2000a, 2003c; Miyamoto et al., 1998).

9. CLINICAL APPLICATIONS OF ABPM

Hypertension is a common chronic condition assuminglyaffecting up to 40% of all adults. The actual prevalence ofindividuals with hypertension, i.e., those at high CVDrisk, is unknown, as all current statistics are based onunreliable clinic BP measurements. One needs to beaware that the joint prevalence of masked normotensionand masked hypertension in the adult population asdefined here, i.e., by incorporating the asleep and notonly the awake SBP/DBP means for classification, is>35% (Hermida et al., 2012a; Ríos et al., 2013). Moreover,with an estimated 30% prevalence of non-dipping withinthe normotensive BP range (Hermida et al., 2002a), >20%

FIGURE 11. Circadian 90% tolerance intervals for SBP (top) andDBP (bottom) derived from a reference population of 504 normo-tensive non-pregnant women and an additional 235 normotensivepregnant women assessed by 48-h ABPM in their second trimesterof pregnancy (14 to 27 wks gestation). Updated from Ayala &Hermida (2013).

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of the population might be “normotensive non-dippers”(Hermida et al., 2013e). Therefore, relying on clinic BPmeasurements, or even at-home self-measurements, forthe identification of high-risk subjects as currently rec-ommended (Chobanian et al., 2003; Mancia et al.,2007a; Pickering et al., 2005), disregarding the vital infor-mation pertaining to circadian BP patterning and theasleep BP level, leads to potential misclassification ofup to 50% of all evaluated individuals. With these con-siderations in mind, ABPM must be considered thegold standard for the diagnosis of true hypertensionand the accurate assessment of CVD risk in the generalpopulation. Nevertheless, due to the documented highprevalence of blunted nighttime BP decline and associ-ated elevated CVD risk, individuals with specific clinicalconditions must be given priority for ABPM evaluation.These include, among others, those with secondary andresistant hypertension, those who are elderly andobese, and those diagnosed with diabetes, CKD, meta-bolic syndrome (MS), or obstructive sleep apnea andother sleep disorders.

9.1. Secondary HypertensionOne of the major advantages of identifying by ABPM therather simple pattern that describes the 24-h BP variationis that departure from the normal dipper profile couldsignify overt pathology. Alteration of the circadianrhythm of the neurohumoral factors that affect the auto-nomic nervous and cardiovascular systems, secondary tovarious pathological conditions, results in persistentchange of the 24-h BP pattern (Fabbian et al., 2013;Hermida et al., 2002a, 2007d; Portaluppi & Smolensky,2007; Portaluppi et al., 1996, 2012; Smolensky et al.,2007, 2012). A high prevalence of nocturnal hypertensionand/or reduced sleep-time relative BP decline (non-dipping) or even asleep BP above the awake BP mean(riser BP pattern) has been reported, apart from otherconditions described more extensively in the followingsections, in patients with orthostatic autonomic failure(Mann et al., 1983), Shy-Drager syndrome (Martinelliet al., 1981), vascular dementia (Tohgi et al., 1991), Alz-heimer-type dementia (Otsuka et al., 1990), cerebralatrophy (Tominaga et al., 1995), phaeochromocytoma(Littler & Honour, 1979), autonomic neuropathy(Cabezas-Cerrato et al., 2009; Cardoso et al., 2008;Hornung et al., 1989; Ikeda et al., 1993; Monteagudoet al., 1996; Schalekamp et al., 1985; Spallone et al.,1993, 2001, 2007), cerebrovascular disease (Matsumuraet al., 1993; Sander & Klingelhöfer, 1994; Shimadaet al., 1990, 1992; Stoica & Enulescu, 1983), ischemic ar-terial disease after carotid endarterectomy (Asmar et al.,1994), neurogenic hypertension (Franklin et al., 1986),fatal familial insomnia (Portaluppi et al., 1994a, 1994b),catecholamine-producing tumors (Dabrowska et al.,1990; Imai et al., 1988a; Isshiki et al., 1986; Oishi et al.,1988; Statius van Eps et al., 1994), Cushing’s syndrome(Imai et al., 1988b), exogenous glucocorticoid adminis-tration (Imai et al., 1989; van de Borne et al., 1993),

mineralocorticoid excess syndromes (Imai et al., 1992;Veglio et al., 1993; White & Malchoff, 1992), Addison’sdisease (Fallo et al., 1994), pseudohypoparathyroidism(Brickman et al., 1990), normotensive and hypertensiveasthma (Franz et al., 1992), chronic renal failure(Cottone et al., 1995; Del Rosso et al., 1994; Hayashiet al., 1993; Heber et al., 1989; Imai et al., 1992;Middeke et al., 1989, 1991; Portaluppi et al., 1990, 1991;Rosansky, 1991; Timio et al., 1993, 1995; Torffvit &Agardh, 1993), salt-sensitive essential hypertension (dela Sierra et al., 1995; Uzu et al., 1996, 1999), essential hy-pertension with left ventricular hypertrophy (Kuwajimaet al., 1992; Verdecchia et al., 1990) or albuminuria(Opsahl et al., 1988), and with renal (Soergel et al.,1992), liver (Taler et al., 1995; van de Borne et al.,1993), and cardiac transplantation related to immuno-suppressive treatment (Dart et al., 1992; Idema et al.,1994a, 1994b; Reeves et al., 1986; Sehested et al., 1992;van de Borne et al., 1992b), congestive heart failure(Caruana et al., 1988; Portaluppi et al., 1992a; Suzukiet al., 1992; van de Borne et al., 1992a), and recombinanthuman erythropoietin therapy (van de Borne, 1992c). Acircadian profile characterized by daytime hypertensionand nighttime hypotension has been described in hemo-dynamic brain infarction associated with prolonged dis-turbance of the blood-brain barrier (Sander &Klingelhofer, 1993). In these patients, the range of vari-ation in BP between the awake and asleep BP meanswas significantly increased from expected. The highlyprevalent altered 24-h BP variation in all these clinicalconditions indicates ABPM is the recommended goldstandard for the diagnosis and CVD risk assessment inpatients with suspected secondary hypertension.

9.2. Resistant Hypertension: Diagnostic and TreatmentIssuesHypertension is currently defined as resistant to treat-ment when a therapeutic plan that includes attention tolifestyle measures and prescription of ≥3 hypertensionmedications (ideally including a diuretic unless contrain-dicated) in therapeutic doses fails to sufficiently lowerSBP and DBP (Calhoun et al., 2008; Chobanian et al.,2003; Fagard, 2012; Mancia et al., 2007a). As defined,resistant hypertension includes also patients with con-trolled BP when treated with >3 medications, i.e., allpatients treated with ≥4 BP-lowering medicationsshould be considered resistant to treatment, irrespec-tively of their BP. This definition, based on unreliableclinic BP determinations, lacks relevant informationfor the proper identification of patients truly resistant totreatment. Therefore, below we propose a more appro-priate and complete definition of resistant hypertension.

Patients with resistant hypertension are at a greaterrisk for stroke, renal insufficiency, and CVD events thanare those for whom BP is responsive to and well con-trolled by therapeutic interventions (Ayala et al., 2013a;Calhoun et al., 2008; Cuspidi et al., 2001). The currentlyaccepted definition of resistant hypertension, presented

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above, relies solely on conventional daytime clinic BPmeasurements. However, published reports documentthe correlation between BP level and target organdamage, CVD risk, and long-term prognosis is fargreater for ABPM than clinical BP measurements (Ayala& Hermida, 2013; Clement et al., 2003; Dolan et al.,2005; Eguchi et al., 2008; Hansen et al., 2007; Hermida& Ayala, 2002, 2004, 2010; Hermida et al., 2011c, 2012a,2012b, 2013b; Minutolo et al., 2011; Perloff et al., 1983;Salles et al., 2008; Staessen et al., 1999; Verdecchiaet al., 1994). Additionally, recent findings (Ríos et al.,2013) reveal the classification of patients as isolated-office, masked, and true resistant hypertension cannotbe based on the comparison of clinic and home BPmeasurements or the awake BP mean derived fromABPM, as is often the case in the available literaturethat, based on misleading current guidelines, totally dis-regards the highly significant prognostic value of thenighttime BP (see Section 5).

Therapeutic strategies for resistant hypertensioncurrently include prescription of additional medicationsor exchanging one medication for a new one in thesearch for a potentially better synergistic combination(Calhoun et al., 2008; Mancia et al., 2007a). Based onthe published literature, it is common for a large pro-portion of hypertensive patients, including those withresistant hypertension, to ingest all their hypertensionmedications in the morning (de la Sierra et al., 2009,2011; Hermida et al., 2002c, 2005b, 2008a, 2010c; Mux-feldt et al., 2003; Salles et al., 2008). In resistant hyperten-sion, however, shifting the ingestion of the complete dailydose of one or more hypertension medications tobedtime, as compared to the ingestion of all medicationsupon-waking, has been prospectively shown by ABPM tosignificantly improve BP control, in particular, to de-crease the sleep-time BP and prevalence of non-dipping (Hermida et al., 2008). Most important, recentlyreported results pertaining to resistant hypertensionpatients who participated in theMAPEC Study documentboth significantly better ambulatory BP control and CVDrisk reduction in patients randomized to ingest the com-plete daily dose of ≥1 hypertension medications atbedtime than in those randomized to ingest all suchmedications upon awakening (Ayala et al., 2013a;Hermida et al., 2010b, 2013g).

Using 24-h ABPM, Muxfeldt et al. (2003) reported a69% prevalence of non-dipping in resistant hypertensionpatients who presumably ingested all medications in themorning. In another much larger cross-sectional study,Hermida et al. (2010c) assessed the impact of BP-lower-ing treatment-time on 1794 resistant hypertensionpatients evaluated by 48-h ABPM. The proportion of con-trolled patients was significantly higher (31.9 vs. 23.1%;p < .001) and the prevalence of non-dipping significantlylower (40 vs. 83%; p < .001) among those who routinelyingested the full daily dose of ≥1 hypertension medi-cations at bedtime than in those who always ingestedall their medications upon awakening. More recently,

Hermida et al. (2013j) evaluated 2899 resistant hyperten-sion patients enrolled in the on-going Hygia Project(Ayala et al., 2013b; Crespo JJ et al., 2013; Mojón et al.,2013; Moyá et al., 2013; Ríos et al., 2013); 1084 of themwere ingesting all their hypertension medications uponawakening (awakening-regimen), 1436 were ingestingthe full daily dose of ≥1 of their medications at bedtime(bedtime-regimen), and 379 were ingesting split equaldoses of ≥1 medications twice-daily, upon awakeningand at bedtime (BID-regimen). The sleep-time relativeSBP and DBP decline was significantly attenuated bythe awakening- and BID-therapy regimens (p < .001),resulting in significantly higher prevalence of non-dipping in these two treatment groups (80.5 and 77.3%,respectively) than in the bedtime-regimen group(54.4%; p < .001 between groups). Additionally, theprevalence of the riser BP pattern, associated withhighest CVD risk, was much greater, 31.0 and 29.8%,respectively, among patients of the upon-awakeningand BID-treatment regimens, compared to thebedtime-treatment regimen (17.6%; p < .001 betweengroups). Thus, in resistant hypertension, ingestion ofthe same medications BID neither improves ambulatoryBP control nor reduces the prevalence of non-dipping;thus, the BID-treatment regimen should be avoided.Moreover, this treatment strategy cannot in anyway beconsidered hypertension chronotherapy, i.e., the timingof medications according to circadian rhythms to opti-mize their desire effects and minimize or avoid comple-tely their adverse effects.

Collectively, the findings of the above cited studiesindicate a bedtime hypertension medication regimen,in conjunction with proper patient evaluation by ABPMto corroborate the diagnosis of true resistant hyperten-sion, should be the therapeutic scheme of choice forpatients who, by conventional cuff methods (and in theabsence of the application of ABPM) and an inappropri-ate morning-treatment regimen, may have been mistak-enly judged to be resistant to therapy. Finally, thesefindings also indicate the definition of resistant hyper-tension must be modified by taking treatment-time intoconsideration; accordingly, a patient should be categor-ized as resistant to treatment if the ABPM-determinedawake and/or asleep SBP or DBP means are greaterthan the reference diagnostic thresholds (Table 3) wheningesting ≥3 hypertension medications of differentclasses (ideally including a diuretic unless contraindi-cated), with at least one of them ingested as a fulldaily dose at bedtime; patients with properly controlledawake and asleep SBP/DBP means when treated with ≥4medications are also resistant to treatment.

9.3 Elderly PatientsSeveral reports document the prognostic value of ABPMin the elderly (Burr et al., 2008; Palmas et al., 2006,2009; Staessen et al., 1999). Additionally, some studiesreport a reduction in sleep-time relative BP declinetowards a more non-dipping pattern in elderly

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hypertensive patients, assumingly associated with the di-minished production of vasoactive peptides, alteredendothelial function, sleep disturbances, and athero-sclerosis, among other causes (Di Iorio et al., 1999; Man-fredini et al., 1996a; O’Sullivan et al., 2003; Portaluppiet al., 1992b, 1994b, 1996; Smolensky et al., 2007, 2012;Trasforini et al., 1991). In fact, increasing age is an inde-pendent marker of non-dipping, even after correctionfor other significant confounders of reduced estimatedglomerular filtration rate, diabetes, reduced HDL-choles-terol, and elevated urinary albumin excretion (Ayala et al.,2013b). This correction is necessary because, comparedto younger hypertensives, elderly patients more fre-quently have diagnoses of albuminuria, CKD, obstructivesleep apnea,MS, anemia, and/orobesity, all conditions inwhich non-dipping is more frequently observed(Hermida et al., 2013a; Portaluppi et al., 1990; Smolensky& Portaluppi, 1999; Smolensky et al., 2007, 2012). None-theless, among the published studies the prevalence ofnon-dipping in older patients is highly variable; thus, itsexact prevalence is uncertain.

A recent cross-sectional study involved 6147 hyperten-sive patients of diverse age evaluated by 48-h ABPM, with2137 being ≥60 yrs of age (Hermida et al., 2013a). At thetime of ABPM, 1809 patients were newly diagnosed asbeing hypertensive and were not yet under treatment,2641 were diagnosed as being hypertensive and ingestedall their prescribed BP-lowering medications upon awa-kening, and another 1697 such patients ingested thefull daily dose of ≥1 hypertension medications atbedtime. The prevalence of non-dipping was signifi-cantly higher in older than younger patients (63.1 vs.41.1%; p < .001). However, the largest differencebetween the age groups was in the prevalence of theriser BP pattern, 19.9 vs. 4.9% in older and youngerpatients, respectively (p < .001). The sleep-time relativeSBP decline was mainly unchanged until ∼40 yrs ofage, and then significantly and progressively decreasedwith increasing age at the rate of .28%/yr (p < .001),reaching a minimum SBP decline of 4.38 ± .47% (mean± SD) in patients ≥75 yrs of age. Treated compared tountreated patients showed lower awake and asleep SBPmeans, although the predictable changes of SBP andDBP with age were equivalent in both groups. As a con-sequence, there were no significant differences betweenuntreated and treated patients regarding changes withage of the sleep-time relative SBP and DBP declines.However, the asleep SBP and DBP means were signifi-cantly lower (p < .001) and the sleep-time relative SBPand DBP decline significantly greater (p < .001) at allages in patients ingesting ≥1 BP-lowering medicationsat bedtime as compared to those ingesting all medi-cations upon awakening (Hermida et al., 2013a).

In conclusion, this large cross-sectional study ofhypertensive patients evaluated by 48-h ABPM demon-strated significantly increased prevalence of a bluntednighttime BP decline with increasing age ≥40 yrs. Theprevalence of the riser BP pattern, associated with the

highest CVD risk among all other possible circadian BPpatterns, was four-fold more prevalent in patients ≥60yrs of age than in ones <60 yrs. Indeed, an elevatedasleep BP mean was the major basis for making the diag-nosis of hypertension and/or lack of adequate ambula-tory BP control among older patients. Moreover,patients of all ages who ingested ≥1 hypertension medi-cations at bedtime in comparison to patients whoingested all of them upon awakening had an attenuatedprevalence of blunted nighttime BP decline. Hence, theproper therapeutic approach for elderly hypertensivesshould not neglect differences in their treatment require-ments, which includes the optimal time-of-day schedul-ing of medications, as dictated by the specific features ofthe individual 24-h BP pattern (Hermida et al., 2013c).

Collectively, these findings indicate elderly subjects, ata threshold age even <60 yrs, should be evaluated byABPM to corroborate the diagnosis of hypertension,ensure proper evaluation of CVD risk associated withalterations of the 24-h BP pattern, and establish themost appropriate timed therapeutic scheme to increaseCVD event-free survival (Hermida et al., 2010b, 2011b,2011c, 2011d, 2013g).

9.4. DiabetesThere is strong association between diabetes and risk ofend-organ damage, stroke, and CVDmorbidity and mor-tality (American Diabetes Association, 2012). Bluntedsleep-time BP decline, characteristic of the non-dippingpattern, is thought to be more common in patients withthan without diabetes (Afsar et al., 2007; Ayala et al.,2013b; Chau et al., 1994; Cuspidi et al., 2006; Equiluz-Bruck et al., 1996; Fogari et al., 1993; Ikeda et al., 1993;Palmas et al., 2008; Pistrosch et al., 2007; Rutter et al.,2000; Wiegman et al., 1990), and this, in turn, mightalso be associated with the elevated CVD risk in diabetes.Nonetheless, the prevalence of non-dipping in diabetesis highly variable among the reported studies; thus, itsexact prevalence is uncertain. Among other factors, thismight be due to differences in the studied populations(normotensive subjects, untreated hypertensives,treated hypertensives), relatively small sample sizes, defi-nition of daytime and nighttime periods by arbitrary fixedclock-hour spans, and frequent reliance only on a single,low-reproducible, 24-h ABPM evaluation per participant.

A recent cross-sectional study of 12 765 hypertensivepatients, including 2954 with type 2 diabetes, evaluatedby 48-h ABPM documented ambulatory SBP was signifi-cantly higher in patients with than without diabetes,mainly during the hours of nighttime sleep and initialhours after morning awakening; ambulatory DBP,however, was significantly lower in patients with dia-betes, mainly during the hours of daytime activity(Ayala et al., 2013b). Differing trends for SBP and DBPbetween groups resulted in large differences in ambula-tory PP, it being significantly greater (p < .001) through-out the entire 24 h in patients with diabetes, even aftercorrecting for age. Age-independent elevated clinic and

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ambulatory PP in patients with diabetes has been re-ported in several previous studies, also documenting aclose relationship in diabetes between elevated PP andincreased CVD risk (Cockcroft et al., 2005; Foucanet al., 2005; Nakano et al., 2005; Palmas et al., 2006;Schram et al., 2002). Elevated PP, indicative of the stiff-ness of the large arteries, has been identified as an inde-pendent marker of CVD risk, mainly for myocardialinfarction, congestive heart failure, and CVD deaths(Benetos et al., 1997; Blacher et al., 2000; Franklin et al.,1999; Verdecchia et al., 1998, 2001). Furthermore, Ayalaet al. (2013b) found the prevalence of non-dipping tobe significantly higher in patients with than without dia-betes (62.1 vs. 45.9%; p < .001). Largest differencebetween groups was in the prevalence of the riser BPpattern, 19.9 vs. 8.1% in patients with and without dia-betes, respectively (p < .001). Elevated asleep SBP meanwas the major basis for the diagnosis of hypertensionand/or inadequate BP control among patientswith diabetes; thus, among the uncontrolled hyperten-sive patients with diabetes, 89.2% exhibitednocturnal hypertension.

Further evaluation of patients of the same study withdiabetes who were under treatment for their hyperten-sion at the time when 48-h ABPM was performedrevealed, in addition, that those ingesting ≥1medicationsat bedtime versus those ingesting all medications uponawakening had lower likelihood of CKD; had significantlylower albumin/creatinine ratio, glucose, total cholesterol,and LDL-cholesterol; plus had higher estimated glomer-ular filtration rate and HDL-cholesterol (Moyá et al.,2013). Ingestion of ≥1 medications at bedtime was alsosignificantly associated with lower asleep SBP and DBPmeans than treatment with all medications upon awak-ening; thus, the sleep-time relative SBP and DBPdecline was significantly attenuated in patients ingestingall BP-lowering medications upon awakening (p < .001).As a result, the prevalence of non-dipping was signifi-cantly higher when all hypertension medications wereingested upon awakening (68.6%) than when ≥1 ofthem were ingested at bedtime (55.8%; p < .001between groups), and even further attenuated (49.7%)when all of them were ingested at bedtime (p < .001).Additionally, prevalence of the riser BP pattern wasmuch greater (23.6%) among patients ingesting all suchmedications upon awakening, compared to those ingest-ing some (20.0%) or all of them at bedtime (12.2%;p < .001 between groups). The latter group also showedsignificantly higher prevalence of properly controlledambulatory BP (p < .001) that was achieved by a signifi-cantly lower number of hypertension medications(p < .001) compared to patients ingesting all such medi-cations upon awakening (Moyá et al., 2013).

These findings are clinically relevant since non-dipping is related to an increase in end-organ injuryand CVD events in patients with diabetes (Astrup et al.,2007; Bouhanick et al., 2008; Eguchi et al., 2008;Hermida et al., 2011b, 2012b; Nakano et al., 1998;

Sturrock et al., 2000). Furthermore, it has been recentlydocumented that the progressive reduction of theasleep BP mean, a novel therapeutic target best achievedby a bedtime hypertension therapeutic strategy (Hermida& Smolensky, 2004; Hermida et al., 2005a, 2007a, 2010b,2011a, 2013c; Portaluppi & Smolensky, 2010; Portaluppiet al., 2012; Smolensky et al., 2010, 2012), is the most sig-nificant predictor of CVD event-free survival (Ayala et al.,2013a; Hermida et al., 2010b, 2011b, 2011c, 2011d,2013b), particularly in patients with type 2 diabetes(Hermida et al., 2012b). Thus, it is noteworthy that therecent 2012 update of the “standards of medical care indiabetes and clinical practice recommendations” fromthe American Diabetes Association indicates the needto “administer one ormore antihypertensivemedicationsat bedtime (level of evidence A)”when treating hyperten-sive patients with diabetes (American Diabetes Associ-ation, 2012).

In summary, the asleep SBP mean is significantlylower and the prevalence of a blunted nighttime BPdecline highly attenuated, i.e., lower prevalence ofmarkers of CVD risk, plus the metabolic profile is mark-edly improved in patients with type 2 diabetesmanaged by a therapeutic strategy that entails the inges-tion of ≥1 of their hypertension medications at bedtimethan those managed by one that entails the ingestion ofall of them upon awakening. These collective findingsindicate bedtime hypertension treatment, in conjunctionwith proper patient evaluation by ABPM to corroboratethe diagnosis of hypertension, should be the strategy ofchoice for patients with type 2 diabetes.

9.5. Obesity and Metabolic SyndromeThe Third Report of the National Cholesterol EducationProgram Expert Panel on Detection, Evaluation, andTreatment of High Blood Cholesterol in Adults (ATP-III)(Grundy et al., 2005) proposed a working definition ofMS based on the presence of at least three of the five fol-lowing factors: elevated waist circumference (≥102 cmmen/ ≥ 88 cm women), elevated triglycerides (≥150 mg/dl, or drug treatment for elevated triglycerides),reduced HDL-cholesterol (<40 mg/dl men/ < 50 mg/dlwomen, or drug treatment for HDL-cholesterol), elevatedclinic BP (SBP ≥130 mmHg and/or DBP ≥85 mmHg, orBP-lowering treatment), and elevated fasting glucose(≥100 mg/dl, or treatment for diabetes). These factorshave recently been adopted as a harmonizing definitionof MS in response to earlier discrepancies betweenvarious international societies and organizations(Alberti et al., 2009). Independent of the definition usedfor MS, there is strong association between this conditionand increased risk of coronary heart disease, stroke, andCVD morbidity and mortality (Isomaa et al., 2001; Nino-miya et al., 2004; Ridker et al., 2003; Sattar et al., 2003;Schillaci et al., 2004). Moreover, the individual attributesof MS listed above are associated with markers of organdamage, including left ventricular hypertrophy, diastolicdysfunction, and albuminuria (Cuspidi et al., 2004a; Lind

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et al., 1995; Masugata et al., 2006; Palaniappan et al.,2003; Schillaci et al., 2006).

Although a blunted sleep-time BP decline is highlyprevalent in diabetes (Ayala et al., 2013b), the associationbetween MS and non-dipper BP patterning seems con-troversial (Ayala et al., 2009; Bastos et al., 2007; Cuspidiet al., 2004b, 2005; Foss et al., 2000; Hermida et al.,2009b, 2011e; Mancia et al., 2007b; Tartan et al., 2006;Vyssoulis et al., 2007). For instance, Cuspidi et al.(2004b, 2005) found no significant difference in noctur-nal BP, assessed by two consecutive 24-h ABPM sessions,in untreated hypertensiveMS patients compared to thosewithout MS. In contrast, Tartan et al. (2006) documentedsignificant elevation in nighttime SBP in hypertensivepatients with high MS score, based on numeric gradingof the different factors comprising the ATP-III definitiongiven above; this scorewas also an independent predictorof the non-dipper BP pattern. Corroborating previousfindings on the impact of obesity on impaired circadianBP regulation (Kotsis et al., 2005), abdominal obesitywas also a significant influential factor for the progressivedecrease in sleep-time relative SBP decline (Tartan et al.,2006). Vyssoulis et al. (2007) also found elevated preva-lence of non-dipping in a large group of untreated hyper-tensive MS patients, the prevalence being directly relatedto the number of the defining components of MS ident-ified per patient. However, the relative influence of eachsingle component upon the absence of proper nocturnalBP decline was not explored. Ayala et al. (2009) investi-gated the circadian BP pattern of 2045 non-diabeticuntreated patients with uncomplicated essential hyperten-sion simultaneously evaluated by 48-h ABPMandwrist act-igraphy. Those with MS, 40.7% of the patients, werecharacterized by a significantly higher 48-h SBP mean anda lowerDBPmean as compared to patientswithoutMS. Ac-cordingly, in the MS versus the non-MS patients, ambula-tory PP was significantly elevated during the entire 24 h.The prevalence of an altered non-dipper BP profile wasalso significantly higher in MS than non-MS patients (48.4vs. 36.1%, p < .001). MS patients were also characterized bysignificantly higher concentrations of uric acid, fibrinogen,and hemoglobin as well as leukocyte count and erythrocytesedimentation rate, and by a lower estimated glomerular fil-tration rate, all relevant markers of increased CVD risk.

A recent cross-sectional study of 3352 non-diabetichypertensive patients evaluated by 48-h ABPM andwrist actigraphy (Hermida et al., 2011e) investigated therelationship between MS, circadian time of hypertensiontreatment, and impaired nighttime BP decline. MS waspresent in 52.6% of the treated hypertensives. The preva-lence of an altered non-dipper BP profile was signifi-cantly higher among patients with than without MS(52.0 vs. 39.5%; p < .001). Of particular relevance wasthe finding that non-dipping was significantly moreprevalent among patients ingesting all BP-loweringmedications upon awakening (56.8%) than amongthose ingesting ≥1 of their medications at bedtime(29.1%; p < .001). Finally, non-dipping was found to

be significantly associated with the presence of MS andtreatment upon awakening in a multiple logisticregression model adjusted by significant confoundingfactors, including age, creatinine, erythrocyte sedimen-tation rate, and cigarette smoking (Hermida et al., 2011e).

In summary, the results of recent large studies indicatesignificantly increased prevalence of non-dipping andadditional markers of CVD risk in patients with MSand/or abdominal obesity. Bedtime treatment with ≥1hypertension medications is significantly associatedwith an attenuated prevalence of the high-risk non-dipper BP profile, both in patients with and withoutMS. These collective findings indicate MS and abdominalobesity must be included among the medical conditionsfor which ABPM is recommended to make the diagnosisof hypertension, accurately evaluate CVD risk, and deter-mine the most advantageous therapeutic scheme, thepreference being a bedtime dosing strategy.

9.6. Chronic Kidney Disease (CKD)Hypertension is very common in patients with CKD; itsprevalence increases with diminished glomerular fil-tration rate (GFR), reaching an estimated 86% in patientswith end-stage renal disease (Agarwal et al., 2003). On theother hand, hypertension leads to kidney and othertarget-organ damage through mechanical and oxidativestress on the vascular wall (Portaluppi et al., 2004). Thediagnosis of hypertension in CKD as well as clinicaldecisions regarding treatment of this modifiable con-dition has been made so far using daytime clinic BPmeasurements obtained in the physician’s office. Evenin the most recent guidelines on hypertension in CKD,no proper attention is given to the diagnostic and prog-nostic relevance of ABPM (Kidney Disease, 2012).However, as in the general population, in patients withCKD the correlation between BP level and target organdamage, CVD risk, and long-term prognosis is greaterfor ABPM than clinic BP (Agarwal & Andersen, 2006a,2006b; Hermida et al., 2011d; Minutolo et al., 2011;Tripepi et al., 2005). In addition, there is a strong associ-ation between blunted sleep-time relative BP decline andincreased incidence of fatal and non-fatal CVD events inpatients with CKD (Agarwal & Andersen, 2006a, 2006b;Amar et al., 2000; Hermida et al., 2011d; Liu et al.,2003; Minutolo et al., 2011; Tripepi et al., 2005). Mostimportant, from a therapeutic point of view, are the find-ings of the recent evaluation of a cohort of patients withCKD (Hermida et al., 2011d) from the MAPEC Study(Ayala et al., 2013a; Hermida, 2007; Hermida et al.,2010b, 2011b, 2011c, 2012a, 2012b, 2013b, 2013e,2013g) that enabled investigation of whether CVD riskreduction is more related to the progressive decreaseduring follow-up of the awake or asleep BP mean. Anal-yses of changes in BP during the median 5.4 yrs follow-up revealed 14% CVD risk reduction per 5 mmHgdecrease in the asleep SBP mean (p < .001), independentof changes in clinic BP or any other ambulatory BPparameter (Hermida et al., 2011d).

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Non-dipping is highly prevalent in patients with CKD(Agarwal & Andersen, 2005; Agarwal et al., 2009; CrespoJJ et al., 2013; Davidson et al., 2006; Mojón et al., 2013;Pogue et al., 2009; Portaluppi et al., 1990), although thereported prevalence of non-dipping in CKD is highlyvariable. Such variability is probably due to relativelysmall sample sizes; differences in the diagnosis of CKDbased in some studies on reduced GFR, only, withoutaccounting for elevated urinary albumin excretion; differ-ences in the studied populations according to stage(severity) of CKD; reliance only on a single, low-reproducible, 24-h ABPM evaluation per participant;and definition of daytime and nighttime periods byarbitrary fixed clock-hour spans. Davidson et al. (2006)reported 57.5% prevalence of non-dipping in a retrospec-tive cohort study of 322 patients but without specificationof the exact prevalence of non-dipping among those withCKD. Pogue et al. (2009) conducted a cross-sectional24-h ABPM study of 617 participants with CKD,only defined on the basis of reduced GFR, in theAfrican American Study of Kidney Disease CohortStudy (AASK), finding very high 80.7% prevalence ofnon-dipping. Agarwal & Andersen (2005) evaluated232 elderly patients with CKD, determining theprevalence of non-dipping increased from 60.0% inpatients with stage 2 CKD, to 80.3%, 71.9%, and 71.4%in patients with stage 3, 4, and 5 CKD, respectively(p = .046).

Mojón et al. (2013) recently assessed by 48-h ABPMthe circadian BP pattern of 10 271 hypertensive patientsenrolled in the Hygia Project. Among the participants,3227 had CKD, defined as an estimated GFR <60 ml/min/1.73 m2, albuminuria (urinary albumin excretion≥30 mg/24-h urine, or albumin/creatinine ratio ≥30mg/gCr), or both, at least twice within ≥3 mo (Leveyet al., 2005, 2009; National Kidney Foundation, 2002).In patients with CKD, ambulatory SBP was significantlyelevated (p < .001), mainly during the hours of nighttimesleep, independent of the presence/absence of BP-lower-ing treatment; ambulatory DBP, however, was signifi-cantly higher (p < .001), mainly during the daytime.Differing trends for SBP and DBP between groups re-sulted in large differences in ambulatory PP, it being sig-nificantly greater (p < .001) throughout the entire 24 h inpatients with CKD. The prevalence of non-dipping wassignificantly higher in patients with than without CKD(60.6 vs. 43.2%; p < .001), but the largest differencebetween groups was in the prevalence of the riser BPpattern, 17.6 versus 7.1% in patients with and withoutCKD, respectively (p < .001). The riser BP pattern signifi-cantly and progressively increased from 8.1% amongpatients with stage 1 CKD to a very high 34.9% for thosewith stage 5 CKD. An elevated asleep SBP mean wasthe major basis for the diagnosis of hypertension and/or inadequate BP control among patients with CKD;thus, among the uncontrolled hypertensive patientswith CKD, 90.7% exhibited nocturnal hypertension(Mojón et al., 2013).

Furthermore, analyses of treated hypertensive patientswith CKD revealed ingestion of ≥1 medications atbedtime was significantly associated with lower asleepSBP/DBP means than treatment with all medicationsupon awakening (Crespo JJ et al., 2013). The sleep-timerelative SBP decline was significantly attenuated inpatients who ingested all their hypertension medicationsupon awakening (p < .001). Thus, the prevalence of non-dipping was significantly greater when all medicationswere ingested upon awakening (68.3%) than when theentire daily dose of ≥1 of them was ingested at bedtime(54.2%; p < .001 between groups), and even further atten-uated (47.9%) when all of them were ingested at bedtime(p < .001). Additionally, the prevalence of the riser BPpattern was much greater (21.5%) among patients ingest-ing all their BP-lowering medications upon awakening,compared to those ingesting some (15.7%) or all ofthem at bedtime (10.6%; p < .001 between groups), inde-pendent of CKD severity. Patients of the latter treatment-regimen group also showed a significantly higher preva-lence of properly controlled ambulatory BP (p < .001)that was achieved by a significantly lower number ofhypertension medications (p < .001) compared to thoseingesting all of their hypertension medications uponawakening (Crespo JJ et al., 2013).

In conclusion, patients with CKD show a significantlyelevated prevalence of blunted nocturnal BP decline.Most important, the riser BP pattern is 2.5-fold moreprevalent in CKD, and up to 5-fold more prevalent inend-stage renal disease. Patients with CKD also show sig-nificantly elevated ambulatory PP, reflecting increasedarterial stiffness and, thus, enhanced CVD risk. Further-more, patients with CKD who ingest ≥1 hypertensionmedications at bedtime, as compared to those whoingest all of them upon awakening, show significantlylower asleep SBP/DBP means and attenuated prevalenceof non-dipping, i.e., lower prevalence of these markers ofCVD risk. Collectively, these findings indicate CKD mustbe included among the clinical conditions for whichABPM is recommended for the accurate diagnosis of hy-pertension and assessment of CVD risk, as well as themeans to establish the optimal therapeutic scheme to in-crease CVD event-free survival. In keeping with thecurrent available information, bedtime hypertensiontreatment should be the preferred therapeutic schemefor hypertensive patients with CKD.

9.7. Obstructive Sleep Apnea and Other Sleep DisordersObstructive sleep apnea is a common condition that fre-quently goes undiagnosed (Lugaresi et al., 1983; Pack,1994), either because patients are asymptomatic duringthe daytime (only severe, symptomatic, sleep apnea iseasily detected during clinical visits) or because theysimply do not present themselves to a physician.Apneic snoring through frequent arousals and enhancedsympathetic hyperactivity disrupts sleep architecture andalso induces a non-dipper BP pattern (Pedulla et al.,1995; Portaluppi et al., 1997); thus, undiagnosed sleep-

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disordered breathing might play a role in the genesis ofthe altered BP pattern of some non-dipper hypertensives.This is especially true formale patients, since snoring andapnea are much more prevalent among men thanwomen (Lugaresi et al., 1994; Young et al., 1993). Essen-tial hypertension is also a very frequent condition inpatients with sleep apnea. Therefore, ABPM is rec-ommended for the accurate diagnosis of hypertensionand assessment of CVD risk in all individuals with sus-pected or confirmed sleep disorders.

The non-dipper BP pattern appears to be associatedstrictly with sleep-disordered breathing that is character-ized by apneic snoring, whereas nonapneic snoring isassociated with only minor increase in BP variability(Portaluppi et al., 1997). Unfortunately, a blunted noctur-nal BP fall is a highly unspecific finding (see Section 4.1);accordingly, ABPM is of limited value for making the di-agnosis of obstructive sleep apnea even whenaccompanied by measurement of activity level by wristactigraphy during nighttime sleep, which can providean estimate (albeit a non-specific one since an alterednighttime activity level might possibly be indicative ofother sleep disturbances) of the number of apneas withfairly good approximation (Sadeh et al., 1989). Thus,the gold standard to achieve the diagnosis of apneicsnoring and assess its severity remains polysomnogra-phy, during which incorporated continuous measure-ments of BP with a fully automated instrument ispreferred to discontinuous ABPM. In fact, only polysom-nography can derive complete and simultaneous infor-mation about breathing events, BP changes, and sleeparchitecture, thus permitting differentiation of non-dippers with actual abnormalities in sleep-related BPchanges from subjects whose non-dipper conditionmay be related to other anomalies of entirely differentpathophysiologic origin, e.g., restless leg syndrome, per-iodic limb movements, or even simple insomnia, some-times induced by the monitoring procedure, itself(Portaluppi et al., 2009). Moreover, snoring and non-severe sleep apnea constitute phenomena that vary notonly from minute to minute but also from night tonight, depending on the lifestyle of the patient andbody position during sleep. Hence, discontinuousABPM measurements might not be fully representativeof all the transient changes in BP occurring during thenight in these patients. Instead, a single session of poly-somnography with continuous BP recording detectseven transient anomalies of breathing and BP that arepresent even in mild cases. Thus, in addition to clearlydifferentiating sleep apnea from other sleep-related dis-eases, polysomnography also reveals which patients areat risk of developing more severe sleep-disorderedbreathing and sustained nocturnal hypertension. In anycase, in view of the expected higher target-organdamage and increased CVD risk in non-dippers and thehigh prevalence in the adult population of undiagnoseddisordered breathing during sleep, we recommend as-sessment of the subject’s sleep history as part of the

routine diagnostic screening of hypertension, especiallywhen non-dipping is found by ABPM evaluation. Whenthe patient’s sleep history suggests significant sleep dis-turbance, polysomnography is the appropriate sub-sequent diagnostic step.

9.8. PregnancyPredictable differences in the 24-h BP pattern throughoutgestation have been identified by means of ABPM in bothclinically healthy and hypertensive pregnant women(Ayala & Hermida, 2013). In normotensive pregnancies,BP steadily decreases up to the middle of gestation andthen increases up to the day of delivery. In contrast,women who develop gestational hypertension or pre-eclampsia show a stable BP during the first half of preg-nancy and thereafter a continuous linear BP increaseuntil delivery (Ayala & Hermida, 1997b; Hermida et al.,2001a). Epidemiologic studies have also consistently re-ported sex differences in the 24-h pattern of ambulatoryBP and heart rate (Ben-Dov et al., 2008; Burt et al.,1995; Hermida, 1999; Hermida et al., 2002a, 2002d,2004d; Kagan et al., 2007; Pimenta, 2012; Reckelhoff,2001; Roger et al., 2011; Vriz et al., 1997). Typically,men exhibit a lower heart rate and higher BP thanwomen, the differences being larger for SBP than DBP(Figure 9). Additionally, as early as in the first trimesterof gestation, statistically significant increased 24-h,awake, and asleep SBP and DBP means characterizewomen who during their pregnancy will be complicatedwith gestational hypertension or preeclampsia comparedto those with normal and uncomplicated pregnancies(Ayala et al., 1997a; Benedetto et al., 1996; Hermidaet al., 2000a, 2003c). However, the normally lower BP innon-gravid women as compared to men, additional de-crease in BP during the second trimester of gestation innormotensive but not hypertensive pregnant women,and significant differences in the 24-h BP patternbetween healthy and complicated pregnancies at allgestational ages have yet to be taken into considerationwhen establishing reference BP thresholds for the diag-nosis of hypertension in pregnancy.

Despite the unquestionably high prognostic value ofABPM as compared to conventional clinic BP measure-ments for the prediction of pregnancy outcome, due topoor results from the awkward approach used by manyinvestigators in their attempt to identify by ABPM womenwho might or might not show elevated clinic BP later inpregnancy, the most extended conclusion in the obstetricfield so far is thatABPMdoesnot enable early identificationof gestationalhypertensionorpreeclampsia and, therefore,should not be used in pregnancy (Higgins et al., 1997).

As discussed previously (Section 8.3), the sensitivityand specificity of the early identification of hypertensionin pregnancy based on the awake and asleep SBP/DBPthreshold values provided in Table 4 can be improvedby the use of other indices also derived from ABPM. Inparticular, the tolerance-hyperbaric test has been pro-spectively shown to be a reproducible, non-invasive,

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and highly sensitive test for the early identification of sub-sequent hypertension in pregnancy, including pre-eclampsia (Hermida & Ayala, 2002; Hermida et al.,1998, 2003a, 2004a). ABPM during gestation, commen-cing preferably at the time of the first obstetric examin-ation following positive confirmation of pregnancy, thusprovides sensitive endpoints for early hypertension-related risk assessment and guidance of prophylacticand/or therapeutic intervention. Among these, low-dose aspirin (100 mg/d) ingested regularly at bedtime,but not upon awakening, commencing before 16 wks ofgestation has been shown to efficiently control elevatedgestational ambulatory BP and to significantly reducethe incidence of preeclampsia, gestational hypertension,intrauterine growth retardation, and preterm delivery(Ayala et al., 2013c; Hermida et al., 1997a, 1999, 2003b).Accordingly, ABPM properly executed and analyzedusing the tolerance-hyperbaric test is the recommendedreplacement for unreliable clinic BP measurements;thus, ABPM should be considered as the gold standardfor the diagnosis of hypertension in pregnancy and thescreening of pregnant women at high risk for other com-plications during gestation, such as preeclampsia, fetalgrowth retardation, and preterm delivery.

9.9. Evaluation of Treatment EfficacyAs indicated previously, ABPM is particularly useful fordefining the efficacy of hypertension medications, inindividual patients (Waeber & Brunner, 1999) and alsopopulations of patients taking part in clinical trials(Coats et al., 1996), especially with respect to the admin-istration-time, i.e., awakening versus bedtime, treatmentregimen as a cost-effective means of improving the man-agement of CVD risk (Hermida, 2007; Hermida & Smo-lensky, 2004; Hermida et al., 2005a, 2007a, 2008a,2010b, 2011a, 2011b, 2011d, 2013c; Portaluppi &Hermida, 2007; Portaluppi & Smolensky, 2010; Portalup-pi et al., 2012; Smolensky et al., 2010, 2012).

Several methods are traditionally used to assess theduration of action of BP-lowering medications. Most ofthem aim to quantify the efficacy of the medications interms of the duration and homogeneity of their BP-low-ering effect (Aboy et al., 2005). The prevailing contentiontoday is the optimal control and management of BPshould be based upon therapeutic strategies thatreduce BP in a homogeneous and smooth mannerthroughout the entire 24 h. The trough:peak ratio (TP)and smoothness index (SI) are two popular indices thathave been used for over two decades to evaluate hyper-tensionmedications and also as the basis for their, some-times misleading, marketing campaigns to doctors andpatients (Elliot & Meredith, 1994; Meredith, 1999;Omboni et al., 1995, 1998; Parati et al., 1998). However,in the case of the TP ratio, the use of different methodsof its calculation has resulted in inconsistencies and dis-crepancies in reported values, thereby calling into ques-tion the validity of this index such that its use is notcurrently recommended (Aboy et al., 2005). The main

limitation of the SI is its interpretation. A medicationhaving negligible and poor BP control, but, nonetheless,having a highly homogeneous BP-lowering effect duringthe 24-h dosing interval will have a very large SI. Thus, forthis and other reasons discussed below, the SI is not auseful index to guide the selection of medications tomanage hypertension patients. To overcome thisproblem, some years ago Aboy et al. (2005) proposed anew so-called normalized smoothness index (SI). Inaddition, Aboy et al. (2006a, 2006b) proposed a novelindex for the proper statistical assessment of hyperten-sion medications, both for application to the individualpatient as well as participants of clinical trials, basedupon the reduction, duration, and homogeneity, i.e.,RDH index, of BP-lowering. The advantages of the RDHindex over the TP, SI, and normalized SI have beenclearly documented (Aboy et al., 2006a, 2006b).Accordingly, the RDH index is recommended for theevaluation of treatment efficacy of hypertension medi-cations assessed by ABPM.

International practice guidelines recommend pre-scription of long-acting, once-daily hypertension medi-cations that have 24-h efficacy (Mancia et al., 2007); thisrecommendation is based on the assumptions thesemedications improve adherence to therapy, minimizeBP variability, and provide smoother andmore consistentBP control. As reported in the published literature (see inparticular: de la Sierra et al., 2009; Hermida et al., 2002c)in the absence of individual patient evaluation by ABPM,practicing physicians are prone to treat all hypertensivepatients by a common strategy involving morning-timedosing of once-a-day, long-acting BP-lowering medi-cations. However, morning-time ingestion of a hyperten-sion medication with high 24-h homogeneous andsustained efficacy is unlikely to correct abnormalities ofthe 24-h BP profile; thus, from our perspective this con-stitutes a rationale therapeutic plan only, if any, fordipper hypertensive patients. Taking into considerationthe facts that not all marketed BP-lowering medicationsprovide entirely homogeneous and complete 24-h effi-cacy and that there exists high prevalence of the non-dipper BP pattern in the population (Ayala et al., 2013b;Crespo JJ et al., 2013; Hermida et al., 2013j; Mojónet al., 2013; Moyá et al., 2013; Ríos et al., 2013), the clini-cal practice of treating all hypertensive patients at thesame time of day, by means of a morning once-a-daytherapeutic strategy, necessitates reconsideration.

The graph presented on the left side of Figure 12 rep-resents the SBP pattern (continuous thick line) of anormotensive man whose measurements are plottedrelative to the circadian time-specified tolerance limits(continuous thin lines) calculated from the data of a ref-erence population of normotensive individuals (Hermidaet al., 2004d), as a function of the person’s sex and rest-activity cycle (time expressed in hours after awakening).The dark bar displayed on the lower horizontal axis indi-cates the nighttime sleep span for this person, as deter-mined by wrist actigraphy. The graph shows that SBP is

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within the normotensive range delimited by the upperand lower tolerance limits throughout the 24 h, corrobor-ating the diagnosis of normotension. The awake andasleep SBP means are also below the referencethresholds provided in Table 3 for the diagnosis ofhypertension in uncomplicated men. The sleep-timerelative SBP decline of 17% indicates the individual hasa normal dipper 24-h BP pattern.

The graph shown on the right side of Figure 12 rep-resents the SBP data (dashed thick line) of a differentman. The awake/asleep SBP means of 155/126 mmHgare both above the corresponding reference thresholdvalues for the diagnosis of hypertension. The sleep-time relative SBP decline is 18.5%, indicating he has anormal dipper 24-h BP pattern. The shadowed areadelimited by the upper tolerance limit with regard tothe 24-h SBP profile of this individual represents the

area of BP excess, i.e., HBI, which is 305 mmHg X h,well above the threshold for the diagnosis hypertensionpresented in Table 3 (Hermida et al., 2000b). For com-parative purposes, the graph also includes the 24-h SBPpattern of the normotensive man shown on the left sideof Figure 12 (continuous thick line). Visual inspectionof the graph on the right side of Figure 12 indicates thatnormalizing the BP of the hypertensive dipper patientto the usual ideal pattern of normotensive dipper sub-jects requires lowering of BP homogeneously, in thesame amount, throughout the entire 24 h, as the patient’sBP is consistently elevated throughout the day and nightto a similar extent above the upper limit of the time-varying tolerance limit.

Figure 13 represents two different hypertensivepatients with a non-dipper BP pattern. The data of thepatient presented on the left side reveal awake/asleep

FIGURE 12. Left: 24-h SBP pattern (thick line) of a normotensive dipper man, plotted with respect to circadian time-specified tolerancelimits (continuous thin lines), calculated from a reference population of normotensive individuals as a function of sex and rest-activity cycle.Right: 24-h SBP pattern (dashed thick line) of a hypertensive dipper man, plotted with respect to the circadian time-specified tolerancelimits (continuous thin lines) of the same reference population of normotensive individuals. The shadowed area that is delimited by theupper tolerance limit and the BP profile of this individual represents the area of BP excess (hyperbaric index). For comparative purposes,the graph also includes the SBP pattern of the normotensive man shown in the left panel (continuous thick line).

FIGURE 13. 24-h SBP pattern (dashed thick lines) of two hypertensive non-dipper male patients, plotted with respect to circadian time-specified tolerance limits (continuous thin lines), calculated from a reference population of normotensive individuals as a function of sexand rest-activity cycle. The shadowed areas delimited by the upper tolerance limit and the BP profiles of these individuals represent the areaof BP excess (hyperbaric index). For comparative purposes, the graphs also include the SBP pattern of the normotensive man shown in theleft panel of Figure 12 (continuous thick line).

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SBP means of 143/134 mmHg, sleep-time relative SBPdecline of 6.1%, and BP elevation above the upper refer-ence limit equal to 94% of the 24-h activity-rest span.Normalizing BP to the level and pattern of normoten-sive dipper persons would require reduction of BPthroughout the 24 h, but to a different extent duringthe daytime activity versus nighttime sleep spans inkeeping with the marked non-dipper BP baselineprofile. The data of the patient shown on the rightside of Figure 13 reveal awake/asleep SBP means of131/129 mmHg, indicating isolated nocturnal hyperten-sion; sleep-time relative SBP decline of 1.7%, corre-sponding to non-dipper 24-h BP patterning; and BPexcess mainly during the nighttime sleep period.While this patient is also a “hypertensive non-dipper”,like the one whose data are shown in the left side ofFigure 13, BP control in this case would require reduc-ing BP only during nighttime sleep, as his awake BPmean is already within normal limits. Interestingly,the diagnosis of hypertension for this patient wouldprobably not be established by relying on daytimeclinic BP determinations, alone, or with supplementalat-home self-assessments, since for most of his activityspan he is normotensive.

The graph on the left side of Figure 14 shows the 24-hSBP pattern of yet another male patient with awake/asleep SBP means of 148/112 mmHg and sleep-timerelative SBP decline of 24%, which means he is anextreme-dipper with isolated daytime hypertension.Ambulatory BP control would require efficient treatmentof the awake BP level, only, as shown by comparing thepatient’s BP profile (dashed thick line) with that derivedfor the reference normotensive man whose data areshown on the left side of Figure 12 (continuous thickline). However, one must keep in mind the therapeuticgoal of preserving/increasing towards normal the sleep-time relative BP decline to minimize CVD risk.

Finally, the data of the male patient presented on theright side of Figure 14 reveals awake/asleep SBP meansof 140/150 mmHg and sleep-time relative SBP declineof -7% indicating he has a riser BP pattern. Proper man-agement of this patient entails reduction of BP to thenormotensive range plus restructuring of the 24-hprofile to the desired dipper pattern by means of a thera-peutic strategy (e.g., bedtime medication regimen) thatattenuates the asleep BP mean to a much greater extentthan the awake BP mean.

Collectively, the different cases of hypertensivepatients presented in Figures 12-14 constitute all possible24-h BP patterns in terms of the sleep-time relative SBPdecline, a significant prognostic marker of the risk ofCVD events (Agarwal & Andersen, 2006a, 2006b; Astrupet al., 2007; Ayala et al., 2013a; Boggia et al., 2007;Bouhanick et al., 2008; Brotman et al., 2008; Burr et al.,2008; Dolan et al., 2005; Eguchi et al., 2008; Hermidaet al., 2011b, 2011c, 2011d, 2013b, 2012b; Ingelssonet al., 2006; Kario et al., 2001; Liu et al., 2003; Minutoloet al., 2011; Nakano et al., 1998; Ohkubo et al., 2002;Salles et al., 2008; Sturrock et al., 2000; Tripepi et al.,2005; Verdecchia et al., 1994). Recognition of the prog-nostic value of the sleep-time relative SBP decline andthe asleep SBP mean (Hermida et al., 2011c) highlightsthe limitations and deficiencies of clinic BP measurmentas a valid diagnostic procedure. Moreover, it calls intoquestion the use of clinic BP, at-home self-measurments,and even the ABPM-derived 24-h BP mean as a reliablemeasure of the efficacy of BP-lowering medications. Byconsidering the regulation (i.e., normalization) of the24-h BP pattern as a worthy therapeutic target as ameans of reducing CVD risk (Hermida et al., 2011c), itshould be obvious (Figures 12-14) that one cannot rec-ommend the same hypertension medication, in thesame dose, and at the same, usually morning, time ofday as the optimal unique therapeutic strategy for all

FIGURE 14. 24-h SBP pattern (dashed thick lines) of a hypertensive extreme-dipper male patient (left) and a male hypertensive riserpatient (right), plotted with respect to circadian time-specified tolerance limits (continuous thin lines), calculated from a reference popu-lation of normotensive individuals as a function of sex and rest-activity cycle. The shadowed areas delimited by the upper tolerance limitand the BP profiles of these individuals represent the area of BP excess (hyperbaric index). For comparative purposes, the graphs alsoinclude the SBP pattern of the normotensive man shown in the left panel of Figure 12 (continuous thick line).

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hypertensive patients. Indeed, the examples presented inFigures 12-14 illustrate the rationale for the use in adultpatients of ABPM to correctly diagnose hypertension,devise optimal treatment regimen, and assess attainmentof desired therapeutic goals.

In hypertensive patients, pharmacologic therapyshould take into account the seldom considered, yetcrucial, variable of treatment-time (with respect to therest-activity pattern of each individual patient) to opti-mally manage and normalize the features of the ABPM-determined 24-h BP pattern that are indicative of targettissue injury and CVD risk. Given the fact the teachingof medical and pharmaceutical sciences today continuesto be based exclusively on the concept of homeostasis, i.e., constancy of biological functions and processes, it isnot surprising that most practitioners continue toassume when, i.e., the time of day, once-a-day medi-cations are ingested is of little or no importance(Morgan, 2009; Parati & Bilo, 2010). An extensive reviewof ingestion-time (i.e., circadian rhythm-dependent)influences on both the desired and undesired effects ofhypertension therapies (Hermida et al., 2013c) showssuch an assumption is not only invalid, at least whenawakening versus bedtime administration times are com-pared, but that it is possible to significantly improve theclinical management of hypertension simply by selectingthe correct time of treatment, and without any additionalfinancial cost to patients or public and private health in-surance agencies that would accrue in many cases by theunnecessary prescription of an increased dose ornumber of therapeutic agents due to improper timing(Hermida et al., 2013g). The chronotherapy of conven-tional hypertension medications thus constitutes a cost-effective strategy for: (i) enhancing the control of awakeand asleep SBP and DBP levels, (ii) normalizing thedipping status of their 24-h patterning, and (iii) poten-tially reducing the risk of CVD events and end-organinjury, for example, to the blood vessels and tissues ofthe heart, brain, kidney, and retina (Ayala et al., 2013a;Hermida et al., 2010b, 2011b, 2011c, 2011d, 2013g).

10. ABPM: PRACTICAL CONSIDERATIONS

10.1. Sampling Rate and Duration of ABPMMost past ABPM patient studies were performed withmeasurements gathered every 15 to 60 min over asingle 24-h span, mainly using mean BP values as criteriato diagnose hypertension (Chobanian et al., 2003; Headet al., 2012; Mancia et al., 2007; Pickering et al., 2005)and assess hypertension therapy (Waeber & Brunner,1999). In actuality, the sampling requirements forABPM have only been occasionally addressed (Enström& Pennert, 2001; Hermida & Ayala, 2003; Hermidaet al., 2007c, 2013d). Previous reports have documentedthe expected increased reproducibility of mean BPvalues associated with the increased number of BPmeasurements per 24 h, i.e., greater sampling rate(Mancia et al., 1994). In addition, ABPM has been also

validated against direct intra-arterial BP measurement,documenting that sampling at 30- to 60-min intervalsprecisely reproduces the “true” beat-to-beat mean BPvalues (di Rienzo et al., 1983).

Themajority of these previous studies have focused on24-h ABPM to primarily investigate only the influence ofBP sampling rate on reproducibility of 24-h mean BPvalues. Thus, most past studies have not evaluated theimpact of the duration of ABPM on the reproducibilityof results. Along these lines, the findings of previousstudies have already documented advantages of extend-ing the duration of ABPM from 24 to ≥48 h in terms ofthe reproducibility of derived clinical parameters(Hermida & Ayala, 2003; Hermida et al., 2002b, 2007c,2013d; Mochizuki et al., 1998; Tamura et al., 1990). Insummary, these studies have consistently documentedthe reproducibility of BP characteristics, includingmean BP values and sleep-time relative BP decline(measure of BP dipping), depends markedly on the dur-ation, and to a much lesser extent on the frequency, ofBP sampling.

A recent study evaluated the influence of the duration(48 vs. 24 h) and sampling rate of BPmeasurement (fromevery 20 to 30 min up to every 2 h) on the prognosticvalue of ABPM utilizing the data from the prospectiveMAPEC Study in which 3344 participants whose baselineBP ranged from normotension to sustained hypertensionwere systematically evaluated by periodic, at leastannually, 48-h ABPM (Hermida et al., 2013d). TheABPM profiles of these participants were modified togenerate reconstructed time series of identical 48-h dur-ation but with data sampled at different intervals – every 1or 2 h – or shorter time series for just the first 24-h spanwith data sampled at the original rate, i.e., at 20- to 30-min intervals. The authors compared the reproducibilityof the 48-h, awake, and asleep BP means, and of thesleep-time relative BP decline derived from the completeBP profiles (original 48-h time series with BP measure-ments obtained at 20- to 30-min intervals from eachparticipant) against each set of modified BP series.Additionally, the Cox proportional-hazard model,adjusted for significant confounding variables, wasused to estimate the HRwith 95% CI for events associatedwith each tested potential prognostic BP parameter, cal-culated from the original complete 48-h BP profiles andfrom each set of modified BP series.

As an illustrative example, Figure 15 shows the limitsof agreement for the asleep means of SBP (top) andDBP (bottom) of the original complete 48-h ABPM pro-files versus the modified ABPM series, i.e., less-densesampling of either one BP measurement per hour for48 h or the original sampling rate of one BP measure-ment per 20 to 30 min for the first 24-h span. EachBland-Altman plot represents the difference betweenthe asleep BP mean calculated from the original seriesand the value calculated from the modified series(in the vertical axis), plotted against the average ofthose two values (in the horizontal axis) (Bland &

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Altman, 1986, 1995). The average of the individual differ-ences in the asleep BP mean was slightly, but, nonethe-less, significantly greater for data sampled every 20 to30 min during the first 24 h than for the reconstructedtime series that simulated data sampled every 1 h for48 h (.3 ± 4.4 vs. -.1 ± 1.6 mmHg in asleep SBP mean; .2± 3.0 vs. -.1 ± 1.4 mmHg in asleep DBP mean; p < .001).Of more direct clinical relevance, Figure 15 further illus-trates the asleep SBP and DBP means obtained from theoriginal complete 48-h ABPM profiles were much betterreproduced with data sampled every 1 h for 48 h (timeseries composed of up to 48 of the maximum original128 BP measurements/participant; right panels ofFigure 15) than with the data obtained at the originalsampling rate of 20- to 30-min intervals for the first 24h, only (time series composed of up to 64 BP measure-ments/participant; left panels of Figure 15). In particular,reduction of ABPM duration to just 24 h resulted in verysignificant error, in the range of -21.4 to +23.9 mmHg,totally unacceptable in clinical practice, in estimatingthe asleep SBP mean, the most significant prognosticmarker of CVD events. Similar findings related to theadvantages of extending the duration of ABPM versus in-creasing the sampling rate were documented for the esti-mation of the 48-h and awake BP means and sleep-timerelative BP decline (Hermida et al., 2013d). Additionally,Cox proportional-hazard analyses revealed a comparableHR formean BP values and sleep-time relative BP decline

derived from the original complete 48-h ABPM profilesand those modified to simulate a sampling rate of oneBP measurement every 1 or 2 h for 48 h. However,when the duration of ABPM was reduced from 48 toonly 24 h, the HRs were markedly overestimated forSBP and underestimated for DBP (Hermida et al., 2013d).

This study on the impact of the duration and the fre-quency of sampling by ABPM on the reproducibilityand accurate estimation of BP parameters currentlyused to establish the diagnosis of hypertension, evaluatepatient response to treatment, and assess CVD risk fullycorroborates previous findings (Hermida & Ayala, 2003;Hermida et al., 2002b, 2007c; Tamura et al., 1990),thereby establishing the estimation of BP indices ismuch more dependent on the duration than samplingrate of ABPM. The HR of CVD events associated with in-creased ambulatory BP is less accurately estimated byrelying on 24-h than 48-h ABPM, indicating ABPM con-ducted for only 24 h may be insufficient to reliablymake the diagnosis of hypertension, identify dippingstatus, evaluate treatment efficacy, and, most important,stratify CVD risk. These collective findings indicateABPM should ideally be performed at least hourly fortwo consecutive 24-h periods to achieve best reproduci-bility of mean BP values and to accurately classifydipping status. Moreover, expanding the length of moni-toring to 48 h, even at the reduced sampling rate of, e.g.,one measurement per hour that does not compromise

FIGURE 15. Bland-Altman plots assessing agreement in estimates of the asleep means of SBP (top) and DBP (bottom) for data originallysampled by ABPM every 20 to 30 min for 48 consecutive hours versus those for modified time series reconstructed with data sampling every1 h for 48 consecutive hours (right), or at the original rate of every 20 to 30 min for the first 24 h only (left). Dotted horizontal line of each plotrepresents the average of the differences across the entire studied population. Dashed lines represent the values of the average difference ±2SD (assumingly containing 95% of the individual values). Updated from Hermida et al. (2013d).

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accurate determination of the indices of the 24-h BPprofile, does not impact patient compliance (Hermida& Ayala, 2003; Hermida et al., 2002a, 200b), renderingABPM an individually reproducible approach for properBP measurement.

10.2. Time Interval between Repeated ABPM EvaluationsABPM is the recommended means for the diagnosis oftrue hypertension, proper CVD risk assessment, andevaluation of treatment efficacy in the general population.Moreover, among the different individual parametersderived from ABPM, the asleep SBP mean is the mostsignificant predictor of CVD events, both individually aswell as jointly when combined with other ABPM-derivedpotential prognostic markers (Hermida et al., 2011c).Most important, the progressive decrease in the asleepBP mean is the most significant predictor of event-freeinterval (Ayala et al., 2013a; Hermida et al., 2010b,2011b, 2011c, 2011d, 2012b, 2013b). Accordingly, ABPMshould be considered as a requirement for systematicfollow-up of individual subjects, and this, in turn, requiresa standard protocol for repeated ABPMevaluations. So far,periodic (at least yearly) 48-h ABPM evaluations on thesame subjects have been performed in the MAPECStudy (Hermida et al., 2010b, 2011b, 2011c, 2011d) andthe on-going Hygia Project (Ayala et al., 2013b; Crespo JJet al., 2013; Hermida et al., 2013j; Mojón et al., 2013;Moyá et al., 2013; Ríos et al., 2013).

As a general guide, the following protocol is rec-ommended for periodic evaluation and follow-up ofpatients by ABPM: (i) for uncomplicated persons witheither normotension or masked normotension, accord-ing to the ambulatory BP reference thresholds listed inTable 3, and unaffected by compelling clinical conditionsassociated with increased CVD risk – including diabetes,CKD, and past CVD events – ABPM should be repeatedwithin 2 yrs; the time interval should be reduced to 1 yrfor complicated normotensive subjects; (ii) for hyperten-sive patients, diagnosed according to the ambulatory BPreference thresholds given in Table 3 and whose thera-peutic regimen is modified in any way (prescription oftreatment to naïve patients, prescription of additionalmedications to previously treated patients, exchange ofmedications, change of dose or time-of-day of medi-cations, etc.), ABPM should be repeated preferablywithin the ensuing 3 mo; (iii) for hypertensive patientswhose BP is established to be properly controlled accord-ing to the ambulatory BP reference thresholds shown inTable 3 and whose therapeutic regimen, therefore,necessitates no modification, ABPM should be repeatedevery 6 mo (complicated patients) to every 12 mo(uncomplicated patients).

10.3. Editing and Validation of ABPMAs previously discussed in more extensive detail (Section3), ABPM should not be analyzed in terms of the clocktime of BP sampling, neither on a population nor on anindividual basis. Proper synchronization of BP data so

that they are expressed in terms of the actual rest-activitycycle of the individual evaluated, e.g., hours frombedtime or hours after awakening, is strongly rec-ommended. In so doing, information on the rest-activitycycle must be properly collected from each personundergoing ABPM evaluation, either by requestingthe individual to keep a diary or, preferably, by wristactigraphy.

Although not free from controversy (O’Brien et al.,2003), it is recommended that ABPM profiles be editedto correct for measurement errors and outliers. Severalmethods for the editing of ABPM-derived data havebeen proposed and evaluated in terms of reproducibility(Winnicki et al., 1997). As a general rule, SBP readings>250 or <70 mmHg, DBP >150 or <40 mmHg, and PP(difference between SBP and DBP) >150 or <20 mmHgshould be eliminated. Moreover, ABPM measurementsmay be invalid when taken during physical exercise, ex-cessive movement, driving, or under unusual mood/emotional states.

As a general recommendation, ABPM data seriesshould be considered invalid for analysis if ≥30% of thescheduled measurements are absent, if data are lackingfor >2 consecutive hourly intervals, if data are obtainedwhile patients maintain an irregular rest-activity sched-ule during consecutive 24-h periods of monitoring, or ifthe nighttime sleep span is <6 h or >12 h.

10.4. Requirements for Healthcare Personnel in Charge ofABPMABPM is a specialized diagnostic technique that requiresinitial and periodic updated training to specific protocolsfor both BP measurement and ABPM analysis andinterpretation. Accordingly, only properly trained per-sonnel should perform ABPM. Analyses and interpret-ation of ABPM results, in particular, require propertraining. The recommended approach is to use a standard-ized data entry booklet (DEB) to record patient medicalhistory and, in addition, a separate standardized reportto detail ABPM findings. This helps ensure that all evalu-ated patients undergo equivalent diagnostic proceduresand that healthcare personnel utilize identical criteriaand therapeutic approaches for optimal BP control andCVD risk reduction. Such a standardized approachmight be easily implemented on-line; thus, all patientinformation might be obtained with an electronic DEB,allowing automatic validation programs to check fordata discrepancies in the DEB and by appropriate errormessages to prompt the clinical site staff for verificationor modification of data in question. Most important,ABPM profiles can be analyzed on-line in real time,thus avoiding costly maintenance and actualization ofsoftware programs required to generate an adequateABPM report in keeping with the recommendations pro-vided above in Sections 3, 4, and 8. This approach hasalready proven valuable for conducting not only individ-ualized patient assessments but also long-term popu-lation-based morbidity and mortality outcome studies

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(Ayala et al., 2013b; Crespo JJ et al., 2013; Hermida et al.,2013j; Mojón et al., 2013; Moyá et al., 2013; Ríos et al.,2013).

10.5. Maintenance and Utilization of ABPM DevicesABPM should be performed using only properly vali-dated devices that have been verified to meet publishedinternational standards (American National Standard,2009; O’Brien et al., 1993, 2010). ABPM devices shouldbe calibrated regularly, at least yearly. The internalbattery of each ABPM device should be checked regularlyand replaced as needed.

At the time of initializing the device for use in a newpatient, trained personnel must program the correctsampling interval for daytime and nighttime measure-ments, confirm the internal clock of the computer is setto the correct date and clock time, and set the ABPMdevice to the so-called “blind function”, i.e., to blockdisplay of BP measurements to avoid potential additionalstress to the patient. Some devices sound a warning tonejust preceding each BP measurement; this feature mustbe switched off during the nighttime span to minimizesleep disturbances. To ensure BP measurement through-out the entire monitoring time span, use of rechargeable,e.g., nickel metal hydride, batteries is highly rec-ommended. Since these batteries have little memoryeffect, they can be recharged many times to theirmaximum capacity thereby enabling the ABPM deviceto operate during many consecutive days (Ayala et al.,2013b; Hermida et al., 2004d). The use of rechargeablebatteries saves great expense (>750$/yr per ABPMdevice) as compared to the use of alkaline batteries thatrequires replacement prior to every ABPM application.The batteries should be removed when the ABPMdevice is not in use.

It is essential to choose the correct cuff size to avoidmeasurement errors due to use of inadequately sizedcuffs. Proper cuff size must be determined by measure-ment of the upper arm circumference at each studyvisit. The BP cuff should be worn on the non-dominantarm and an actigraph, if used, on the dominant wrist.The cuff and the handling bag for the ABPM devicemust be washed regularly to ensure hygienic conditions.

10.6. Patient InstructionsIndividuals should be given detailed information aboutthe advantages of ABPM, procedure of BP measurement,and handling and operation of the ABPM device. Theprovision of a written set of instructions is recommendedto complement verbal instructions provided by trainedhealthcare personnel. Patients must be aware of thepotential discomfort of ABPM mainly during sleep, theprogrammed sampling rate, the setting of the blind-func-tion (so that the non-display of BP readings is not mistak-enly interpreted asmalfunctioning of the device), and theprogrammed feature on most devices to automaticallyrepeat a BP measurement 2 min after the occurrenceof a measurement error. Finally, patients should be

informed of the precise date and time the ABPM deviceis to be returned to the clinical setting.

Patients must be specifically instructed to: keep thecuff at heart level, cease moving or talking, keep thearm still and relaxed, and breathe normally whenthe cuff starts to inflate; fit and properly adjust the cuffto the non-dominant arm; preferably wear a thin layerof cotton clothing under the cuff to minimize risk ofbruising and thus increase compliance; switch thedevice off every time it is removed, e.g., to shower/bathe, change clothes, etc., and switch it on again there-after; keep the device on during nighttime sleep and notswitch it off; adhere to usual activities with minimalrestrictions, but to keep a similar activity-rest scheduleand avoid daytime napping during the days of ABPM;avoid activities that might interfere with operation ofthe device or ascertainment of representative BP values;and fill in all required entries in the diary.

All individuals undergoing ABPM must maintain adiary listing the time of retiring to bed at night, awakeningin the morning, consumption of meals, ingestion of allmedications, participation in exercise, and episodes ofunusual physical activity, mood/emotional states, andother atypical events thatmight affect BP. This individual-ized information can be utilized to edit the ABPM data, ifrequired, and to determine the commencement and ter-mination of the daytime activity and nighttime sleepspans to accurately derive the awake and asleep BPmeans of each subject, after referring each individual’sclock-hour BP values to, e.g., hours after awakeningfrom nighttime sleep.

10.7. Scheduling of Patient Appointments for ABPMTo optimize the utilization of the available ABPMdevices,it is recommended that healthcare personnel in charge ofABPM keep a calendar of the date and clock time of allprogrammed appointments in keeping with the follow-up recommendations presented in Section 10.2. A suffi-cient amount of time, typically more than an hour, is rec-ommended between the scheduled return time of thedevice and the next appointment time for its applicationto another patient. This allows for possible delays bypatients in returning the device and permits sufficienttime for personnel to transfer measurement data fromthe device to the computer, perform data analyses, gen-erate the medical report, and re-initialize the device.Special seasonal periods, such as holidays, local festiv-ities, and vacation time, should be avoided when sched-uling a patient for ABPM. Special attention should begiven when performing ABPM on shiftworkers; ideally,ABPM should be avoided during the first days followinga non-daytime work shift.

11. CONCLUSIONS

Worldwide, elevated BP is responsible for at least 7.6million, i.e., nearly 13%, of all deaths annually, morethan any other medical condition, and for 57 million,

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i.e., approximately 3.7%, of total disability-adjusted lifeyrs. Moreover, around 54% of strokes and 47% of coron-ary heart disease cases are attributed to suboptimal BPcontrol (Arima et al., 2011). The worldwide reportedprevalence of hypertension, based only on clinic BPmeasurements, is >40%, while in most Western countriesthe prevalence of poor hypertension control is extremelyhigh, >65%. Thus, according to the WHO, uncontrolledBP is epidemic worldwide, affecting in total an estimated1 billion adults ≥25 yrs. Unfortunately, the prevalence ofBP control has not improved in recent years, despite theincreased intensity of therapy and progressive increase inthe proportion of patients treated with ≥2 hypertensionmedications (Catalá-López et al., 2012; Tocci et al.,2012). Hence, the pharmacotherapy of hypertension ismarkedly suboptimal and must be improved by: (i)proper early identification of at-risk individuals, morefeasible with ABPM as clearly summarized above anddocumented in numerous publications (e.g., Ayala &Hermida, 2013; Clement et al., 2003; Dolan et al., 2005;Eguchi et al., 2008; Hansen et al., 2007; Hermida &Ayala, 2002, 2004, 2010; Hermida et al., 2011c, 2012a,2012b, 2013b; Minutolo et al., 2011; Perloff et al., 1983;Salles et al., 2008; Staessen et al., 1999; Verdecchiaet al., 1994); (ii) establishment of more cost-effective in-dividualized therapeutic schemes, more feasible by thecombined use of ABPM and bedtime chronotherapy regi-mens (Hermida & Ayala, 2009; Hermida & Smolensky,2004; Hermida et al., 2003d, 2004c, 2005a, 2007a,2007b, 2007e, 2008b, 2009a, 2010a, 2010b, 2010c,2011a, 2011c, 2013c; Portaluppi & Smolensky, 2010; Por-taluppi et al., 2012; Smolensky & Portaluppi, 1999; Smo-lensky et al., 2010, 2012); and (iii) targeting therapy to theclinical indices of the BP 24-h pattern most sensitive andrepresentative of the elevated vulnerability of the bloodvessels of the brain, heart, kidney, retina, etc., to injuryand patient CVD disability and death (Ayala et al.,2013a; Hermida et al., 2010b, 2011b, 2011c, 2011d,2012b, 2013b).

The objective of treating hypertension is to reduce BPin a manner that diminishes or, ideally, eliminates therisk of end-organ injury, maternal/fetal vulnerability,and CVD events associated with BP elevation. The epide-miologic relationship between BP and CVD risk is con-sistent, although far stronger for ambulatory than clinicBP measurements (Ayala & Hermida, 2013; Clementet al., 2003; Dolan et al., 2005; Eguchi et al., 2008;Hansen et al., 2007; Hermida et al., 2011c, 2012a,2012b, 2013b; Minutolo et al., 2011; Perloff et al., 1983;Salles et al., 2008; Staessen et al., 1999; Verdecchiaet al., 1994). The salutary effect of BP reduction is consis-tent and, to a certain extent, independent of the interven-tions used to achieve it. Unfortunately, popular currenthypertension therapy strategies do not entirely eliminatethe CVD hazards associated with BP elevation. Rather, itonly decreases them by approximately one-third – a note-worthy but clearly suboptimal result (Gradman, 2011).Review of the CVD-event incidence of past hypertension

outcome studies reveals that a relatively low level ofmajor CVD events has been achieved only in thosetrials that specifically enrolled low-risk hypertensivepatients, i.e., trials that avoided the inclusion of higherrisk persons, such as ones ≥65 yrs of age, with diabetes,CKD, previous CVD events, and/or advanced organdamage (Zanchetti, 2009). Collectively, the findings ofpast outcome CVD morbidity and mortality studies en-tailing such high-risk patients indicate current hyperten-sion therapy strategies fail to sufficiently lower CVD risk,giving rise to the belief that they have a “residual CVDrisk” that cannot be reduced by conventional treatment(Mancia et al., 2009). This questionable conclusion(Hermida et al., 2013g) is based on the evaluation ofdata from outcome studies of hypertensive patientsprescribed a morning-time regimen for their once-a-day BP-lowering medications and assessed for theextent of BP control on the unique basis of a verylimited number of unreliable in-clinic daytime cuffmeasurements.

The design of all these previous studies and theirassociated conclusions disregard the facts: (i) correlationbetween BP level and CVD risk is stronger for ambulatorythan clinic BP, and (ii) BP-lowering efficacy and effects onthe 24-h BP pattern of different classes of hypertensionmedications exhibit statistically and clinically significant,morning versus evening, treatment-time differences(Hermida et al., 2007a, 2010b, 2013c; Smolensky & Porta-luppi, 1999; Smolensky et al., 2010, 2012). Independentprospective studies report the sleep-time BPmean deter-mined by ABPM is a much better independent predictorof CVD events than either the awake or 24-h BP means(Agarwal & Andersen, 2006a, 2006b; Amar et al., 2000;Ayala et al., 2013a; Ben-Dov et al., 2007; Boggia et al.,2007; Bouhanick et al., 2008; Dolan et al., 2005; Fagardet al., 2008; Fan et al., 2010; Hermida et al., 2011c,2012b, 2013b, 2013e; Kikuya et al., 2005; Minutoloet al., 2011). Most important, recently published findingsof theMAPEC Study document, based upon periodic sys-tematic 48-h ABPM evaluation of all participants during amedian follow-up of 5.6 yrs, progressive decrease in theasleep SBP mean and increase in the sleep-time relativeSBP decline towards a more normal dipper BP pattern– two new important therapeutic targets that require ap-propriate patient evaluation by ABPM and best achievedby a bedtime hypertension treatment schedule – are themost significant predictors of reduced CVD risk(Hermida et al., 2010b, 2011b, 2011c, 2011d). In thisregard, the MAPEC Study found patients randomized toa bedtime hypertension medication regimen benefitedfrom a very significant reduction in the HR of CVDevents, i.e., to the risk level of normotensive subjects, in-dependent of the number of hypertension medicationsrequired to achieve proper ambulatory BP control(Hermida et al., 2013g). These findings challenge themedical concept, and also the common belief of manydoctors, of “residual CVD risk” of patients that, in fact,may be a consequential artifact of morning-time

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treatment strategies coupled with inadequate patientevaluation procedures based only upon a very restrictednumber of daytime clinic BP measurements, even if sup-plemented with at-home patient self-assessments.

While current international guidelines recognize theprognostic value of ABPM, at this time it is recommendedonly in a very limited number of clinical circumstances,specifically, suspected isolated-office hypertension,resistant hypertension, hypotensive symptoms aftertreatment, episodic hypertension, and autonomic dys-function (Mancia et al., 2007a). The recent update ofthe guidelines for the clinical management of primaryhypertension in adults from the National Institute forHealth and Clinical Excellence (NICE), however, pro-poses for the very first time the need for ABPM to cor-roborate the diagnosis of hypertension in all adults withelevated clinic BP (National Institute for Health andClinical Excellence, 2011). This recommendation, as out-lined, is mainly based on the potential reduction ofhealthcare expenditures, primarily, those associatedwith unnecessary long-term pharmacotherapy and man-agement of its adverse effects, through identification ofpeople with masked normotension, i.e., individuals erro-neously considered to be hypertensive based solely uponthe manifestation of high clinic BP values (Lovibondet al., 2011). The NICE guidelines, however, fail to recog-nize the high prevalence and markedly elevated CVD riskof patients with either masked hypertension and/or“non-dipping normotension”. Moreover, they rec-ommend the diagnosis of hypertension be based onlyupon ABPM-determined daytime SBP/DBP means≥135/85 mmHg, thus totally disregarding the most rel-evant information of the asleep SBP/DBP means(Figures 6-8). In other words, the indisputable medicaladvance represented by the wider recommendation inthe NICE guidelines to employ ABPM for the diagnosisof hypertension is tarnished by the restriction thatABPM be performed exclusively on subjects with ele-vated clinic BP and with emphasis only upon the use ofthe daytime SBP and DBP means as diagnostic criteria,which are bound to fail to properly identify individualshaving masked hypertension, nocturnal hypertension,and “normotensive” non-dipper BP profile. Relying onclinic BP measurements, at-home self-measurements,or even the ABPM-determined 24-h mean for identifi-cation of high-risk subjects, disregarding the vital infor-mation of circadian BP patterning and asleep BP level,is likely to result in potential misclassification of asmany as 50% of all evaluated individuals. Accordingly,the proper interpretation of the data derived fromaround-the-clock ABPM must include examination ofthe sleep as well as daytime BP values as the gold stand-ard for the diagnosis of true hypertension and, thus, therecommended means for accurate end-organ and CVDrisk assessment in the general population, independentof clinic BP measurements.

The potential utility and applicability in the UnitedStates (US) of the NICE guidelines for extended, although

yet arguably limited, ABPM use for the diagnosis of hy-pertension have been questioned in a recent editorial(Bloch & Basile, 2011). According to its authors, the con-cerns regarding the use of ABPM in the US are: (i) lack ofwide availability of ABPM devices in primary care prac-tice settings; (ii) ABPM is presently only covered by insur-ance companies to determine the presence/absence of“isolated-office hypertension”, i.e., masked normoten-sion; (iii) routine application of ABPM to diagnose hyper-tension is impractical due to an insufficient number ofABPM devices available at specialized centers andneeded time-consuming training to properly applythem and interpreted the data they generate (Bloch &Basile, 2011). These “concerns” reduce down to the pre-sumed “elevated cost” of ABPM, although without ac-counting for the cost-savings derived from the moreaccurate diagnosis and comprehensive treatment of hy-pertension with the associated reduction of CVD riskand events; and the obvious need for training. In thepast, such unjustified objections were made againstother clinically significant biomedical and technologicaladvances involving improved patient management,which if rejected would have greatly inhibited severalbreakthroughs routinely utilized today in clinical medi-cine to enhance patient disease-free interval andquality life.

Concerns have been raised about the expense ofimplementing ABPM patient programs in the US andelsewhere, but without evidence in the absence of appro-priate economic assessment studies. However, thoseknowledgeable of the many advantages of around-the-clock application of ABPM are equally concerned aboutthe misguided reliance upon daytime cuff measures,not only in the clinic as it relates to individual patienthealth, but also hypertension research, and its associatedcost-effectiveness and pertinence to public health policy.For example, Giles et al. (2012) recommend 24-h ABPMreplace the long-used conventional daytime cuff BPmethod to gather BP data in all future US NationalHealth and Nutritional Examination Surveys (NHANES)to estimate with greater accuracy the prevalence andcontrol of hypertension in the general population. Therationale for this recommendation is concern about“white coat” and “masked” hypertension effects con-founding national survey data. Nonetheless, Giles et al.(2012) do not specify exactly how the derived 24-hABPM data are to be reduced and interpreted. Wesupport the recommendations set forth by Giles et al.(2012), not only with respect to the utilization of ABPMfor future NHANES, but also for the assessment of newhypertension therapies, as has been the requirement bygovernmental agencies for several decades. In addition,around-the-clock ABPM methods ought to be requiredfor all US National Heart, Lung, and Blood Institute(NIH) funded hypertension research and also that spon-sored by government agencies elsewhere. Moreover, inconsideration of the huge prevalence of hypertensionin the general population, ABPM ought to be instituted

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in clinical medicine as the gold standard for the diagnosisof hypertension, determining CVD and other hyperten-sion-associated risk, and evaluating attainment of treat-ment goals, in adherence with the procedures, indices(including the sleep-time BP decline and sleep-timeSBP/DBP means), and thresholds specified in the pre-ceding sections of this document.

Recently, the NIH announced the funding of a $114multicenter randomized clinical trial, based entirelyupon clinical cuff BP measures, aimed at determiningwhether reducing clinic BP levels below the currently rec-ommended ones results in further reduction of CVD risk,in keeping with the ongoing debate relating to whether ornot there exists a J-curve relationship between treatment-achieved BP and CVD risk (see Section 7). Themajor goalof this long-term outcomes study, the Systolic BloodPressure Intervention Trial (SPRINT; information avail-able at www.clinicaltrials.gov and www.nhlbi.nih.gov/news/press-releases), is to determine if hypertensivepatients treated to achieve a daytime clinic SBP ofeither <140 mmHg (standard group) versus <120mmHg (treatment group) differ significantly in CVDrisk and disease–free interval; those randomized to thetreatment group are expected to be managed onaverage by 3-4 hypertension medications, while thoserandomized to the standard group are expected to bemanaged on average by 2 medications. The merit ofthis study seems dubious, since several previous ratherlarge-scale studies (Appel et al., 2010; Bangalore et al.,2010; Cushman et al., 2010; Okumura et al., 2005;TRANSCEND Investigators, 2008; Voko et al., 1999;Yusuf et al., 2008) have already shown that increasingthe number of medications ingested in the morning –with the goal of aggressively decreasing daytime clinicBP, in the absence of appropriate evaluation of the treat-ment effect on the indices of the 24-h BP pattern – poten-tially increases, not decreases, CVD risk. Thus, this NIH-funded hypertension treatment study, based entirely ontraditional clinical cuff BP determinations, consideredby some opinion leaders to be an outdated approachwhen compared to the more modern, comprehensive,and accurate around-the-clock ABPM one, appears tobe an incredible waste of money, time, and effort. Fur-thermore, based on the findings of themost recently pub-lished ABPM-based outcome studies, themost importanttreatment targets ought to be the: (i) asleep SBP and DBPmeans, and (ii) sleep-time relative BP decline, two clini-cally meaningful parameters of the 24-h BP pattern bestmanaged by a bedtime-treatment regimen. This uniquetreatment-time strategy that best achieves asleep BPcontrol as the primary therapeutic goal has been shownin prospective investigations to reduce clinic SBP <120mmHg without increasing CVD risk (Hermida et al.,2013g, 2013h). This finding is in exact opposition tothat mistakenly predicted by the J-curve phenomenonbased entirely on the relationship established betweendaytime clinic BP, only, and CVD risk in patientstreated with a morning-time schedule of hypertension

medications (Hermida et al., 2013h). Without proper24-h patient evaluation by ABPM and by pursuinglower clinic BP through increase in the number of medi-cations prescribed for morning ingestion, the SPRINTstudy, unfortunately for patients randomized to themore aggressive treatment group, could very well culmi-nate in the unintended consequence of increased CVDevents. Moreover, considering the current cost of anABPM device, number of patients/yr that can be evalu-ated by a 48-h ABPM study, plus average expected per-formance life in years per device, the $114 milliongranted to the SPRINT study investigators would enableassessment in total of 136 million American adults!The overall very low cost/very high benefit ratio ofABPM and its proven ability to significantly reduce therisk of fatal and non-fatal CVD events and enhancedisease-free interval, are among the issues that haveeither yet to be recognized or properly appreciated by ad-ministrators of private and government health insuranceprograms. The incorporation of around-the-clock ABPMinto state-of-the-art medical programs should be the pre-ferred means of significantly increasing the accuracy ofdiagnosing hypertension, assessing CVD risk, and estab-lishing optimal individualized therapeutic interventionto minimize injury to all at-risk blood vessels andtissues of the body, improve the early detection of gesta-tional hypertension and prevent associated maternaland fetal risk, and increase CVD event-free interval.

12. ABPM: SUMMARY OF RECOMMENDATIONS

1. Clinic BP for assessment of CVD risk. There areseveral major disadvantages of conventional clinic BPmeasurements; they are: (i) indicative of the BP statusof only a very brief and small fraction of the entire 24-hBP pattern; (ii) affected by several potential sources oferror, including a rather large “white-coat” effect; and(iii), most importantly, unable to provide independentprognostic value to assess CVD morbidity and mortalityrisk when corrected by ABPM measurement. Accord-ingly, clinic BP values should no longer be consideredto be the “gold standard” for the diagnosis of hyperten-sion and assessment of CVD risk.2. BP representation and analysis. Analysis of ABPMdata in terms of clock time of BP sampling can be mis-leading, both in population studies and in individualpatient evaluations. Proper synchronization of BP datato the patient’s specific rest-activity cycle, such as hoursfrom bedtime or hours after awakening, is preferable. Inso doing, accurate information on the rest-activity cyclemust be properly collected from all individuals under-going ABPM evaluation, either by requesting them tomaintain a diary or, preferably, by wrist actigraphy.3. Prognostic value of ABPM-derived characteristics.

3.1. 24-h BP mean for CVD risk assessment. Thecommonly used 24-h BP mean for deciding the diag-nosis of hypertension totally disregards the extremelyvaluable clinical information conveyed by specific

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features of the circadian BP pattern. Individuals withthe same 24-h BPmeanmay display radically differentcircadian BP patterns, ranging from extreme-dipper toriser types, thus constituting markedly different CVDrisk states. Therefore, the 24-h BP mean is insufficientand not recommended formaking the diagnosis of hy-pertension and assessing CVD risk.3.2. Asleep vs. awake BP means for CVD risk as-sessment. Among the different individual parametersderived from ABPM, the asleep SBP mean is the mostsignificant predictor of CVD events, both individuallyand jointly when combined with other ABPM-derived potential prognostic markers. The sleep-timerelative SBP decline adds prognostic value to themodel that already includes the asleep SBP meanand corrected for relevant confounding variables. Ac-cordingly, the asleep, rather than awake, SBP meanderived from ABPM is preferred to diagnose hyperten-sion and assess CVD risk. Most important, the pro-gressive decrease in the asleep BP mean, a noveltherapeutic target that requires accurate evaluationby ABPM, is a highly significant predictor of event-free interval.3.3. Sleep-time relative BP decline vs. dippingclassification. CVD risk increases exponentiallywhen the sleep-time relative SBP decline is <6% andslightly, but not significantly, decreases for declinevalues above this threshold. Accordingly, the sleep-time relative SBP decline as a continuous variable,and not the dipping classification per se that is typi-cally based on an arbitrary 10% threshold value,should be used for appropriate CVD risk assessment.Moreover, the risk of CVD events is different for thesleep-time relative declines of SBP and DBP. There-fore, use of the same 10% threshold value for thesleep-time relative decline of SBP and DBP to categor-ize subjects according to their dipping status is mis-leading and should be avoided.3.4. Prognostic value of other ABPM-derived par-ameters. Additional ABPM-derived parameters, in-cluding the morning BP surge, standard deviation(SD), and ambulatory arterial stiffness index (AASI),add little additional increase in prognostic value tothe asleep SBP mean. Interestingly, a greatermorning BP surge is associated with lower, nothigher, CVD risk, in agreement with the highly sig-nificant association between increased sleep-timerelative BP decline and reduced CVD risk. Further re-search is needed to properly ascertain if the prognos-tic value of the asleep BP mean can be improved byconcomitant use of other ABPM-derived parameters.

4. Masked normotension (also known as isolated-office hypertension). Masked normotension is definedas elevated clinic BP (≥140/90 mmHg) but normalawake and asleep ABPM SBP/DBP means (<135/85 and<120/70 mmHg, respectively). These threshold valuesshould be replaced by those listed in Table 3 for specialpopulations (see Section 8). Classification of subjects in

this category by comparison of clinic with either the 24-h or awake BP mean, disregarding the clinical signifi-cance of the asleep BP mean, is misleading and shouldbe avoided. Accordingly, masked normotension cannotbe defined by comparing clinic BP with at-home self-measurements. The relative CVD risk of subjects withnormal awake and asleep SBP/DBPmeans is low; accord-ingly, the term “isolated-office hypertension” should pre-ferably be replaced by the more appropriate term“masked normotension”.5. Masked hypertension. Masked hypertension isdefined as normal clinic BP (<140/90 mmHg) butelevated awake and/or asleep ABPM SBP/DBP means(≥135/85 or ≥120/70 mmHg, respectively). Thesethreshold values should be replaced by those listed inTable 3 for special populations (see Section 8). Classifi-cation of subjects in this category by comparison ofclinic with either the 24-h or awake BP mean, disregard-ing the clinical significance of the asleep BPmean, is mis-leading and should be avoided. Accordingly, maskedhypertension cannot be defined by comparing clinic BPwith at-home self-measurements. When categorizingpatients as masked hypertensive, one needs to be awarethat subjects with an elevated awake BP mean andnormal asleep BP mean are at significantly lower CVDrisk than those with elevated asleep BP.6. Normotensive non-dippers. Non-dippers have sig-nificantly higher CVD risk than dippers, whether theyhave normal or elevated ambulatory BP. Non-dipperswith normal awake and asleep SBP/DBP means, whomight account for >20% of adults, have a similar hazardratio as dippers with elevated ambulatory BP. Accordingly,CVD risk is influenced not only by ambulatory BPelevation, but also by blunted nighttime BP decline, evenwithin the normotensive range, thus supporting ABPM asa requirement for accurate CVD risk assessment in thegeneral population. “Normotensive” individuals with anon-dipper BP profile represent a clear paradox, as thosepersons neither have “normal BP” nor low CVD risk.7. The J-curve phenomenon. The J-shaped relation-ship with CVD risk, described so far only for clinic BPdetermined in patients presumably treated with hyper-tension medications in the morning, does not apply tothe ABPM-determined asleep BP mean, a more signifi-cant predictor of CVD morbidity and mortality than thedaytime clinic BP or ambulatory awake BP mean. More-over, no J-curve relationship is found between CVD riskand achieved clinic BP, awake BP mean, or asleep BPmean in patients managed by a bedtime treatmentregimen, thus suggesting the J-curve is mainly associatedwith over-treatment of patients in the morning with themisdirected therapeutic goal of progressive reductionof clinic BP measurements, while disregarding entirelyasleep BP control.8. References thresholds for ABPM. Referencethresholds for the diagnosis of hypertension shouldbe established taking into consideration documentedfactors significantly affecting BP regulation and

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CVD risk. All the reference thresholds listed belowfor the diagnosis of hypertension, i.e., high CVD risk,should also be used as the therapeutic goal for treatedpatients.

8.1. Reference ABPM thresholds in uncomplicatedmen. Outcome-based ABPM reference thresholdsfor men, in the absence of compelling clinical con-ditions, are 135/85 mmHg for the awake and 120/70 mmHg for the asleep SBP/DBP means.8.2. Reference ABPM thresholds in uncomplicatedwomen. Outcome-based reference thresholds for thediagnosis of hypertension are lower by 10/5 mmHgfor ambulatory SBP/DBP in uncomplicated women,i.e., 125/80 mmHg for the awake and 110/65 mmHgfor the asleep SBP/DBP means.8.3. Reference ABPM thresholds in high-riskpatients. Outcome-based reference thresholds forthe diagnosis of hypertension are lower by 15/10mmHg for ambulatory SBP/DBP in high-risk patients,including those with diabetes, CKD, and/or past CVDevents, i.e., 120/75 mmHg for the awake and 105/60mmHg for the asleep SBP/DBP means.8.4. Reference ABPM thresholds in pregnancy.Conventional clinic BPmeasurements are neither diag-nostic nor sufficiently predictive of the development ofhypertension during gestation or pregnancy outcome.Proper diagnostic thresholds should reflect thenormal and predictable BP changes that occur duringgestation, in particular, the expected diminished BPin pregnant as compared to non-pregnant women. In-dependent of maternal age and parity, the ABPM refer-ence thresholds for identification of hypertension inpregnancy are: 115/70 mmHg for the awake SBP/DBPmeans in the first trimester of pregnancy (<14 wks ges-tation), 115/69 mmHg in the second trimester (14-27wks gestation), and 118/72 mmHg in the third trimester(≥27 wks gestation); and 99/58, 98/56, and 104/60mmHg for the asleep SBP/DBP means in each of therespective trimesters of pregnancy. Alternatively, hyper-tension in pregnancy might be defined as a hyperbaricindex (HBI) ≥15 mmHg X h. The HBI is defined as thetotal area during the entire 24-h period of any givensubject’s ambulatory BP above a time-varyingthreshold defined by a tolerance interval calculated asa function of gestational age and derived fromaround-the-clock ABPM assessment of an appropriatereference population.

9. Clinical applications of ABPM.9.1. ABPM in the general population. The jointprevalence of masked normotension and masked hy-pertension is >35% in the adult population. Moreover,>20% of “normotensive” adults have a non-dipper BPprofile and, thus, are at high CVD risk. Therefore,relying on clinic BP measurements, even when sup-plemented with at-home self-measurements, foridentification of high-risk subjects, disregarding thevital information pertaining to circadian BP patterningand asleep BP level, leads to potential misclassification

of up 50% of all evaluated individuals. Accordingly,ABPM is the gold standard for the diagnosis of true hy-pertension and the accurate assessment of CVD risk inthe general population.9.2. ABPM in secondary hypertension. A highprevalence of nocturnal hypertension and/or non-dipping has been reported, among other conditions,in patients with orthostatic autonomic failure, Shy-Drager syndrome, vascular dementia, Alzheimer-type dementia, cerebral atrophy, phaeochromocyto-ma, autonomic neuropathy, cerebrovascular disease,ischemic arterial disease after carotid endarterectomy,neurogenic hypertension, fatal familial insomnia, cat-echolamine-producing tumors, Cushing’s syndrome,exogenous glucocorticoid administration, mineralo-corticoid excess syndromes, Addison’s disease,pseudohypoparathyroidism, asthma, salt-sensitive es-sential hypertension, essential hypertension withrenal, liver, and cardiac transplantation, congestiveheart failure, and recombinant human erythropoietintherapy. Accordingly, ABPM is the recommended goldstandard for patients with suspected secondaryhypertension, to correctly assess both BP status andCVD risk.9.3. ABPM in resistant hypertension. A patientshould be categorized as resistant to treatment if theABPM-determined awake and/or asleep SBP or DBPmeans are greater than the reference diagnosticthresholds (see Table 3 and Section 8) when ingesting≥3 hypertension medications of different classes(ideally including a diuretic unless contraindicated),with at least one of them ingested as a full daily doseat bedtime. Accordingly, patients with properly con-trolled awake and asleep SBP/DBP means whentreated with ≥4 medications are also resistant to treat-ment. Clinic BP values and at-home self-measure-ments should no longer be used to diagnoseresistant hypertension; according to the above defi-nition, it must be based on ABPM. A bedtime hyper-tension medication regimen, in conjunction withproper patient evaluation by ABPM to corroboratethe diagnosis of true resistant hypertension, shouldbe the preferred therapeutic approach for patientswith resistant hypertension.9.4. ABPM in the elderly. There is progressive in-crease with aging in the prevalence of non-dippingand nocturnal hypertension after 40 yrs of age.Elderly subjects, at a threshold age even <60 yrs,should be evaluated by ABPM to corroborate the diag-nosis of hypertension, ensure proper evaluation ofCVD risk associated with alterations in the 24-h BPpattern, and establish the most appropriate chrono-therapeutic scheme to increase CVD event-free inter-val. In the elderly, bedtime treatment with the entiredaily dose of ≥1 hypertension medications is associ-ated with significantly higher prevalence of properlycontrolled awake and asleep BP means and lowerprevalence of the non-dipper/riser BP pattern.

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Therefore, a bedtime hypertension regimen is the rec-ommended strategy for elderly hypertension patients.9.5. ABPM in diabetes. The prevalence of non-dipping is significantly greater in patients with thanwithout diabetes. Elevated asleep SBP mean is themajor basis for the diagnosis of hypertension and/orsuboptimal BP control among patients with diabetes;thus, among uncontrolled hypertensive patients withdiabetes, >89%might potentially exhibit nocturnal hy-pertension. Accordingly, ABPM is the gold standardfor the proper diagnosis of hypertension and assess-ment of CVD risk in patients with diabetes. In dia-betes, the ingestion of the full daily dose of ≥1 BP-lowering medications at bedtime, compared to the in-gestion of all such medications upon awakening, isassociated with lower asleep BP mean, attenuatedprevalence of non-dipping, and significant reductionin CVD morbidity and mortality. Therefore, bedtimehypertension treatment is the strategy of choice forpatients with diabetes.9.6. ABPM in obesity and metabolic syndrome.There is significantly increased prevalence of non-dipping and other markers of CVD risk in patientswith metabolic syndrome and/or abdominal obesity.Bedtime treatment with the entire daily dose of ≥1 hy-pertension medications is significantly associated withattenuated prevalence of the high-risk non-dipper BPprofile, both in patients with and without metabolicsyndrome. Accordingly, metabolic syndrome andabdominal obesity must be included among themedical conditions for which ABPM is recommendedto make the diagnosis of hypertension, accuratelyevaluate CVD risk, and determine the most advan-tageous therapeutic scheme, the preference being abedtime dosing strategy.9.7. ABPM in chronic kidneydisease (CKD).There issignificantly elevated prevalence of non-dipping inpatients with CKD. Prevalence of the riser BP pattern is2.5-fold greater in CKD, and up to 5-fold greater inend-stage renal disease. Among uncontrolled hyperten-sive patients with CKD, >90% exhibit nocturnal hyper-tension. Patients with CKD also show significantlyelevated ambulatory PP, reflecting increased arterialstiffness and enhanced CVD risk. Furthermore, patientswith CKD who ingest the entire daily dose of ≥1 hyper-tension medications at bedtime, as compared to thosewho ingest all of them upon awakening, show signifi-cantly lower asleep SBP/DBP means and attenuatedprevalence of non-dipping, i.e., lower prevalence ofmarkers of CVD risk. Collectively, these findings indicateCKD must be included among the clinical conditionsfor which ABPM is recommended for the accurate diag-nosis of hypertension and assessment of CVD risk. Inaddition, bedtime treatment should be the preferredtherapeutic scheme for hypertensive patients with CKD.9.8. ABPM in obstructive sleep apnea and othersleep disorders. The non-dipper BP pattern is fre-quent in obstructive sleep apnea, so that undiagnosed

sleep-disordered breathing might play a role in thegenesis of the altered BP pattern of some non-dipperhypertensives. Sleep apnea and arterial hypertensionare frequently associated conditions. Therefore,ABPM is recommended for the accurate diagnosis ofhypertension and assessment of CVD risk in all indi-viduals with suspected or confirmed sleep disorders.Nonetheless, the highly unspecific nature of ablunted nocturnal BP fall makes ABPM, even whenaccompanied by measurement of activity level bywrist actigraphy during nighttime sleep, unsuited foridentifying the diagnosis of obstructive sleep apnea.Thus, the gold standard to achieve the diagnosis ofapneic snoring and to assess its severity remainspolysomnography with incorporated continuous BPmeasurements, which permits also distinguishingsleep apnea from other sleep disturbances. Assess-ment of the subject’s sleep history as part of theroutine diagnostic screening of hypertension ishighly recommended and should not be omittedwhen non-dipping is found by ABPM evaluation.When the patient’s sleep history suggests significantsleep disturbance, polysomnography is the appropri-ate subsequent diagnostic step.9.9. ABPM in pregnancy. ABPM during gestation,commencing preferably at the time of the first obste-tric examination following positive confirmation ofpregnancy, provides sensitive endpoints for early hy-pertension-related risk assessment and guidance ofprophylactic and/or therapeutic intervention. Amongthese, low-dose aspirin (100 mg/d) when ingestedregularly at bedtime, commencing before 16 wks ofgestation, has been shown to efficiently control ele-vated gestational ambulatory BP and to significantlyreduce the incidence of preeclampsia, gestationalhypertension, intrauterine growth retardation, andpreterm delivery. Accordingly, ABPM is the rec-ommended replacement for unreliable clinic BPmeasurements as the gold standard for the diagnosisof hypertension in pregnancy and the screening ofpregnant women at high risk for other hypertension-related complications during gestation, such aspreeclampsia, fetal growth retardation, andpreterm delivery.9.10. ABPM for evaluation of treatment efficacy.ABPM is particularly useful for defining the efficacyof hypertension medication, in individual patientsand also populations of patients taking part in clini-cal trials. The trough:peak ratio and smoothnessindex have too many limitations and are not usefulparameters to guide the selection of medications tomanage hypertension patients. The reduction, dur-ation, and homogeneity (RDH) index is rec-ommended for the evaluation of treatment efficacyof hypertension medications assessed by ABPM. Inhypertensive patients, pharmacologic therapyshould take into account the crucial variable of treat-ment time with respect to the 24-h rest-activity

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pattern of each individual patient to optimallymanage and normalize the features of the ABPM-de-termined circadian BP pattern that are indicative oftarget tissue injury and CVD risk. The chronotherapyof conventional hypertension medications constitutesa cost-effective strategy to enhance control ofdaytime and nighttime SBP and DBP levels, normal-ize dipping status of the 24-h BP pattern, and poten-tially reduce risk of CVD events and end-organ injuryto the blood vessels and tissues of the heart, brain,kidney, and retina.9.11. ABPM in treated patients. The differing CVDrisk of patients categorized in terms of clinic vs. ambu-latory BP measurements indicates ABPM should notbe used for the first-time evaluation of patientsalready treated with 1 or 2 BP-lowering medications.In the absence of a baseline ABPM performed beforeinitiation of treatment, therapy was undoubtedly pre-scribed in keeping with a diagnosis based only uponclinic BP measurements and, therefore, potentiallyhighly misleading. As such, ABPM performed for thevery first time in treated patients is unable to dis-tinguish who, indeed, is hypertensive but properlycontrolled by therapy from those prescribedunnecessary therapy because of masked normoten-sion. These limitations must be taken into consider-ation when performing first-time ABPM in patientstreated with ≤2 medications who cannot be washed-out, e.g., for about 2 wks before ABPM. In principle,first-time evaluation by ABPM should be restricted tountreated subjects and patients treated with ≥3 BP-lowering medications, those who might thus be trulyresistant to treatment if the awake and/or asleep BPmeans are inadequately controlled (see Table 3 andSection 8).

10. ABPM: Practical considerations.10.1. Sampling rate and duration of ABPM.. The reproducibility and reliable estimation ofparameters currently used to establish the diagnosisof hypertension, evaluate patient response totreatment, and assess CVD risk based on ABPM ismuch more dependent on the duration thansampling rate of ABPM.

. ABPM conducted for only 24 h may be insufficientto reliably make the diagnosis of hypertension,identify dipping status, evaluate treatment efficacyand, most important, stratify CVD risk.

. Ideally, ABPM should be performed at least hourlyfor two consecutive 24-h periods to achieve thehighest reproducibility of mean BP values andmost reliable classification of patients according todipping status.

10.2. Time-interval between repeated ABPMevaluations. The following protocol is recommendedfor the periodic evaluation and follow-up of patientsby ABPM:. For uncomplicated persons with either normoten-sion or masked normotension, according to the

ambulatory BP reference thresholds listed inTable 3, and unaffected by compelling clinicalconditions associated with increased CVD risk –including diabetes, CKD, and past CVD events –ABPM should be repeated within 2 yrs; the time in-terval should be reduced to 1 yr for complicatednormotensive subjects.

. For hypertensive patients, diagnosed according tothe ambulatory BP reference thresholds given inTable 3, and whose therapeutic regimen is modi-fied in any way (prescription of treatment tonaïve patients, prescription of additional medi-cations to previously treated patients, exchangeof medications, change of dose or time-of-day ofmedications, etc.), ABPM should be repeated pre-ferably within the ensuing 3 mo.

. For hypertensive patients whose BP is establishedto be properly controlled according to the ambu-latory BP reference thresholds shown in Table 3and whose therapeutic regimen, therefore,necessitates no modification, ABPM should berepeated every 6 mo (complicated patients) toevery 12 mo (uncomplicated patients).

10.3. Editing and validation of ABPM.. Proper synchronization of the BP data so that theyare expressed in terms of the actual rest-activitycycle of the individual evaluated, e.g., hoursfrom bedtime or hours after awakening, isstrongly recommended.

. ABPM profiles should be edited to correct formeasurement errors and outliers.

. ABPM measurements may be invalid when takenduring physical exercise, excessive movement,driving, or under unusual mood/emotional states.

. ABPM data series should be considered invalid foranalysis if:

– ≥ 30% of the scheduled measurements areabsent,

– if data are lacking for >2 consecutive hourlyintervals,

– if data are obtained while patients maintain anirregular rest-activity schedule during the twoconsecutive 24-h periods of monitoring, or

– if the nighttime sleep span is <6 h or >12 h.10.4. Requirements for healthcare personnel incharge of ABPM.. Only properly trained personnel shouldperform ABPM.

. Analyses and interpretation of ABPM results alsorequire proper training.

. The recommended approach is to use a standard-ized data entry booklet for recording the medicalhistory and a standardized ABPM report. Thishelps ensure that all evaluated patients undergoequivalent diagnostic procedures and that health-care personnel utilize identical criteria and thera-peutic approaches for optimal BP control andCVD risk reduction.

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. On-line ABPM evaluation is an approach thathas already proven valuable for conductingindividualized patient assessment and popu-lation-based morbidity and mortality long-termoutcome studies.

10.5. Maintenance and utilization of ABPMdevices.. ABPM should be performed using only properlyvalidated devices that have been verified to meetpublished international standards.

. Devices should be calibrated regularly, atleast yearly.

. The internal battery of each ABPM deviceshould be checked regularly and replacedas needed.

. Trained personnel must program the correctsampling interval for daytime and nighttimemeasurements, confirm the internal clock of thecomputer is set to the correct date and clocktime, ensure the warning tone that signals a BPmeasurement is switched off during the nighttimesleep span, and set the ABPM device to the so-called “blind function”.

. To ensure BP measurement throughout the entiremonitoring span, use of rechargeable batteries ishighly recommended.

. The batteries should be removed when the ABPMdevice is not in use.

. It is essential to choose the correct cuff size toavoid measurement errors due to use of inade-quately sized cuffs.

. Proper cuff size must be determined by measure-ment of the upper arm circumference at eachstudy visit.

. The BP cuff should be worn on the non-dominantarmandanactigraph, if used, on thedominantwrist.

. The cuff and the handling bag for the ABPMdevice must be washed regularly to ensurehygienic conditions.

10.6. Patient instructions.. Patients must be aware of the:

√ Potential discomfort of ABPM mainlyduring sleep.

√ Programmed sampling rate.√ Setting of the blind-function so that the

non-display of BP readings is not mista-kenly interpreted as malfunctioning ofthe device.

√ Programmed feature on most devicesto automatically repeat a BP measurement2 min after the occurrence of ameasurement error.

√ Patients should be informed of the precisedate and time the ABPM device is to be re-turned to the clinical setting.

. Subjects must be specifically instructed to:√ Keep the cuff at heart level, cease moving

or talking, keep the arm still and relaxed,

and breathe normally when the cuff startsto inflate.

√ Fit and properly adjust the cuff to the non-dominant arm.

√ Preferably wear a thin layer of cotton cloth-ing under the cuff to minimize risk of bruis-ing and thus increase compliance.

√ Switch thedeviceoff every time it is removed,e.g., to shower/bathe, change clothes, etc.,and switch it on again thereafter.

√ Keep the device on during nighttime sleepand not switch it off.

√ Adhere to usual activities with minimal re-strictions, but keep a similar activity-restschedule and avoid daytime nappingduring the days of ABPM.

√ Avoid activities that might interfere withoperation of the device or ascertainmentof representative BP values

√ Fill in all required entries in the diary.. Patientsmust keep a diary listing the time of retiringto bed at night, awakening in the morning, con-sumption of meals, ingestion of all medications,participation in exercise, and episodes of unusualphysical activity, mood/emotional states, andother atypical events that might affect BP.

10.7. Scheduling of patient appointments forABPM. To optimize the utilization of the availableABPM devices, it is recommended that healthcarepersonnel in charge of ABPM keep a calendar ofthe date and clock time of all programmedappointments in keeping with the follow-uprecommendations presented in Section 10.2.

Declaration of Interest: The authors report no conflictsof interest.

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Hermida RC, Ayala DE, Iglesias M. (2001a). Predictable blood pressurevariability in healthy and complicated pregnancies. Hypertension38:736–741.

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Hermida RC, Ayala DE, Iglesias M. (2003a). Circadian rhythm of bloodpressure challengues office values as the “gold standard” in the di-agnosis of gestational hypertension. Chronobiol. Int. 20:135–156.

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Hermida RC, Ayala DE, Mojón A, Fernández JR, Alonso I, Aguilar MF,Ucieda R, Iglesias M. (2003c). Differences in circadian bloodpressure variability during gestation between healthy and compli-cated pregnancies. Am. J. Hypertens. 16:200–208.

Hermida RC, Calvo C, Ayala DE, Domínguez MJ, Covelo M, FernándezJR, Mojón A, López JE. (2003d). Administration-time-dependenteffects of valsartan on ambulatory blood pressure in hypertensivesubjects. Hypertension 42:283–290.

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Hermida RC, Ayala DE, Fernández JR, Mojón A, Iglesias M. (2004a).Reproducibility of the tolerance-hyperbaric test for diagnosinghypertension in pregnancy. J. Hypertens. 22:565–572.

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Hermida RC, Calvo C, Ayala DE, Domínguez MJ, Covelo M, FernándezJR, Fontao MJ, López JE. (2004c). Administration-time-dependenteffects of doxazosin GITS on ambulatory blood pressure of hyper-tensive subjects. Chronobiol. Int. 21:277–296.

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Hermida RC, AyalaDE, Calvo C, López JE,MojónA, FontaoMJ, Soler R,Fernández JR. (2005b). Effects of the time of day of antihypertensivetreatment on the ambulatory blood pressure pattern of patientswith resistant hypertension. Hypertension 46:1053–1059.

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Hermida RC, Ayala DE, Fernández JR, Calvo C. (2007b). Comparison ofthe efficacy of morning versus evening administration of telmisar-tan in essential hypertension. Hypertension 50:715–722.

Hermida RC, AyalaDE. Fernandez JR,Mojón A, Calvo C. (2007c). Influ-ence ofmeasurement duration and frequency on ambulatory bloodpressure monitoring. Rev. Esp. Cardiol. 60:131–138.

Hermida RC, Ayala DE, Portaluppi F. (2007d). Circadian variation ofblood pressure: The basis for the chronotherapy of hypertension.Adv. Drug Deliv. Rev. 59:904–922.

Hermida RC, Calvo C, Ayala DE, López JE, Rodríguez M, Chayán L,Mojón A, Fontao MJ. Fernández JR. (2007e). Dose- and adminis-tration-time-dependent effects of nifedipine GITS on ambulatoryblood pressure in hypertensive subjects. Chronobiol. Int.24:471–493.

Hermida RC, Ayala DE, Fernández JR, Calvo C. (2008a). Chronotherapyimproves blood pressure control and reverts the nondipper patternin patients with resistant hypertension. Hypertension 51:69–76.

Hermida RC, Ayala DE, Mojón A, Fernández JR. (2008b). Chronother-apy with nifedipine GITS in hypertensive patients: Improved effi-cacy and safety with bedtime dosing. Am. J. Hypertens. 21:948–954.

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Hermida RC, Chayán L, Ayala DE, Mojón A, Domínguez MJ, FontaoMJ, Soler R, Alonso I, Fernández JR. (2009b). Association of meta-bolic syndrome and blood pressure non-dipping profile in un-treated hypertension. Am. J. Hypertens. 22:307–313.

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Hermida RC, Ayala DE, Mojón A, Fernández JR. (2010b). Influence ofcircadian time of hypertension treatment on cardiovascular risk:Results of the MAPEC study. Chronobiol. Int. 27:1629–1651.

Hermida RC, Ayala DE,Mojón A, Fernández JR. (2010c). Effects of timeof antihypertensive treatment on ambulatory blood pressure andclinical characteristics of subjects with resistant hypertension.Am. J. Hypertens. 23:432–439.

Hermida RC, Ayala DE, Fernández JR, Portaluppi F, Fabbian F, Smo-lensky MH. (2011a). Circadian rhythms in blood pressure regu-lation and optimization of hypertension treatment with ACEinhibitor and ARB medications. Am. J. Hypertens. 24:383–391.

Hermida RC, Ayala DE, Mojón A, Fernández JR. (2011b). Influence oftime of day of blood pressure-lowering treatment on cardiovascularrisk in hypertensive patients with type 2 diabetes. Diabetes Care34:1270–1276.

Hermida RC, Ayala DE, Mojón A, Fernández JR. (2011c). Decreasingsleep-time blood pressure determined by ambulatory monitoringreduces cardiovascular risk. J. Am. Coll. Cardiol. 58:1165–1173.

Hermida RC, Ayala DE, Mojón A, Fernández JR. (2011d). Bedtimedosing of antihypertensive medications reduces cardiovascularrisk in CKD. J. Am. Soc. Nephrol. 22:2313–2321.

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Hermida RC, Ayala DE, Crespo JJ, Mojón A, Chayán L, Fontao MJ,Fernández JR. (2013a). Influence of age and hypertension treat-ment-time on ambulatory blood presure in hypertensive patients.Chronobiol. Int. 30: 176–191.

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