blood pressure variability, cardiovascular risk and antihypertensive treatment

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Current Hypertension Reports ISSN 1522-6417Volume 14Number 5 Curr Hypertens Rep (2012) 14:421-431DOI 10.1007/s11906-012-0290-7

Blood Pressure Variability, CardiovascularRisk, and Risk for Renal DiseaseProgression

Gianfranco Parati, Juan E. Ochoa &Grzegorz Bilo

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ANTIHYPERTENSIVE THERAPY: RENAL INJURY (MR WEIR AND GL BAKRIS, SECTION EDITORS)

Blood Pressure Variability, Cardiovascular Risk, and Riskfor Renal Disease Progression

Gianfranco Parati & Juan E. Ochoa & Grzegorz Bilo

Published online: 18 August 2012# Springer Science+Business Media, LLC 2012

Abstract The adverse cardiovascular consequences of highblood pressure (BP) not only depend on absolute BP values,but also on BP variability (BPV). Evidence has been providedthat independently of mean BP levels, BP variations in theshort- and long-term are associated with the development,progression and severity of cardiac, vascular and renal organdamage, and with an increased risk of CVevents and mortal-ity. Alterations in BPV have also been shown to be predictiveof the development and progression of renal damage, which isof relevance if considering that impaired renal function in ahypertensive patient constitutes a very potent predictor offuture CV events and mortality even in treated subjects. Thisreview will address whether antihypertensive treatmentshould target alterations in BPV, in addition to reducing abso-lute BP levels, in order to achieve the highest CV and renalprotection in hypertensive and renal patients.

Keywords Hypertension . Blood pressure . BP .

Short- and long-term BP variability . Cardiovascular risk .

Cardiovascular morbidity and mortality . Renal diseaseprogression . End-stage renal disease . ESRD . Chronickidney disease . CKD . Arterial hypertension . AmbulatoryBPmonitoring . Home BPmonitoring . Antihypertensivetreatment

Introduction

Over the past 30 years, several observational studies haveindicated that the adverse cardiovascular (CV) consequen-ces of high blood pressure (BP) not only depend on absoluteBP values, but also on BP variability (BPV). Evidenceshown that short-term BP fluctuations are closely associatedwith the development, progression and severity of cardiac,vascular and renal organ damage [1–6], and with an in-creased risk of CV and renal events and of CV mortality[7–12]. More recently, it has also been shown that BPfluctuations over longer time intervals, e.g., between daysor visits, may also have prognostic implications [13–15].

When focusing on the kidney, several studies have shownthat alterations in BPV, independently of mean BP levels,may predict the development and progression of renal dam-age. This is of relevance if considering that the presence ofimpaired renal function based on the finding of a reducedglomerular filtration rate (GFR) or the detection of elevatedurinary albumin excretion rates, in a hypertensive patient,constitutes a very potent predictor of future CV events anddeath even in treated subjects [16–19]. Indeed, impairedrenal function is currently considered a marker of a veryhigh CV risk at any given category of clinical BP [20].Against the background of the current evidence, the ques-tion has been raised whether antihypertensive treatmentshould also be targeted to normalization of alterations in

G. Parati (*)Cardiology and Department of Clinical Medicine and Prevention,University of Milan-Bicocca,P.zza Brescia, 20,Milan, Lombardy 20149, Italye-mail: [email protected]

G. Parati : J. E. Ochoa :G. BiloDepartment of Cardiology,S. Luca Hospital, IRCCS Istituto Auxologico Italiano,P.zza Brescia, 20,Milan, Lombardy 20149, Italy

J. E. Ochoae-mail: [email protected]

G. Biloe-mail: [email protected]

J. E. OchoaDepartment of Clinical Medicine and Prevention,University of Milan-Bicocca,P.zza Brescia, 20,Milan, Lombardy 20149, Italy

Curr Hypertens Rep (2012) 14:421–431DOI 10.1007/s11906-012-0290-7

Author's personal copy

BPVand not merely to control of mean BP values in order toachieve the highest CV and renal protection. Although evi-dence has consistently supported the analysis of BP fluctua-tions over time as a potential tool to improve the therapeuticapproach to hypertension and to assess the efficacy of anti-hypertensive pharmacological treatment, a number of rea-sons have until now prevented the introduction of BPVassessment in the routine clinical management of hyperten-sion. On one hand, the mechanisms responsible for in-creased BPV have not been completely understood [21].On the other hand, although animal studies have indicatedan independent beneficial effect of specific drug classes inreducing BPV and in preventing organ damage, limitedevidence from clinical studies in humans is available toconsistently support that specific treatment strategies mightreduce BPV independently of mean BP reduction and thatthis reduction might protect against organ damage and im-prove outcome [22, 23]. The purpose of the present article isto provide a review on the mechanisms, determinants andprognostic relevance of different types of BPV. Focus isgiven to the relevance of an increased BPV for the devel-opment and progression of renal disease, addressing thequestion of whether BPV should be a target for antihyper-tensive treatment in renal patients.

Mechanisms and Determinants of BPV

BPV is a dynamic and complex phenomenon includingshort- and long-term fluctuations as a result of intricateinteractions among behavioral, environmental, humoral,and neural central or reflex influences, as well as otherpotential contributing factors (Fig. 1). Measures of BPVcan be obtained through different methods, i.e., continuousbeat-to-beat BP recordings, conventional office BP (OBP)measures, 24-h ambulatory BP monitoring (ABPM) orhome BP monitoring (HBPM). BP fluctuations can beassessed over different time intervals, i.e., in the very shortterm (beat-by-beat), in the short term (over 24 h) and in thelong term (day by day, between seasons or visit to visit). It isimportant to highlight these different components and meth-ods, since the mechanisms and determinants influencingeach type of BPV may differ as well as their clinical signif-icance and prognostic implications (Fig. 1).

BP variations in the very short and in the short term mayreflect central and reflex autonomic modulation (i.e., anincreased central sympathetic drive and reduced arterialand cardio-pulmonary reflexes) [24–26]; elastic propertiesof arteries (i.e., a reduced arterial compliance) [23, 27]; theeffects of humoral (insulin, angiotensin II, bradykinin,endothelin-1, nitric oxide), rheological (i.e., blood viscosi-ty), emotional (i.e., psychological stress) and behavioralfactors, including effects associated with postural changes.

BP variations in the short term also include slower BPfluctuations occurring between day and night, which are sig-nificantly influenced both by the subject’s level of activityduring daytime and by the sleep/wakefulness cycle. In thegeneral population, BP falls on average by 10-20 % of day-time values during sleep, a phenomenon referred to as dip-ping. However, in some individuals the nocturnal decrease inBP is blunted (non-dippers, with a fall in nighttime systolicand diastolic BP <10 % of daytime BP) or even increases (socalled risers or “inverted dippers”). Dippers exhibiting a night-time BP fall >20 % are known as extreme dippers [28].Remarkably, the nondipping profile of BP is frequently ac-companied by increased nocturnal mean BP levels (i.e., night-time BP >125/75 mmHg) [28]. Proposed mechanisms for anon-dipping pattern of BP and nocturnal hypertension includean increased sympathetic activity during nighttime [29], adecreased renal sodium excretory ability [30], salt sensitivity[31], an altered breathing patterns during sleep (i.e., obstruc-tive sleep apnea), leptin and insulin resistance [32], endothe-lial dysfunction and glucocorticoid use.

Although long-term BPV (i.e., day by day, visit to visit orseasonal BP variations) has been shown to be a reproducibleand not a random phenomenon [33]; it might not entirelyconsist of spontaneous BP variations, or reflect the same phys-iological CV control mechanisms of short-termBP fluctuations,but it may also be the result of imperfect stability of BP controlin treated subjects (in particular visit-to-visit BP variationsduring follow-up) or reflect the inconstant accuracy of OBPreadings (See Fig. 1) [34]. Indeed, visit-to-visit BPV may beimportantly determined by improper titration/dosing of anti-hypertensive therapy or by errors in BP measurement. Also apoor patients’ compliance with the prescribed therapeutic reg-imen may influence long-term BPVas dose omission or delayin drug intake during the follow-up period may also contributeto an increased day-by-day and visit-to-visit BPV. Finally, long-term BPV has been reported to occur as a consequence ofseasonal climatic changes. When considering OBP values, theaverage of self-BP measurements performed by subjects athome or the mean of 24-h BP values collected by ABPM,systolic and diastolic BP levels have been reported to be lowerduring summer and higher during winter [35]. In addition, it hasalso been reported that in treated hypertensive patients animproper downward titration of the antihypertensive drug reg-imen during summer (which is often performed on the basis ofclinical variations of clinic BP) may reduce the extension of24-h BP coverage and contribute to the nighttime increase inBP levels reported during hot weather in some studies [36].

Assessment of Short-Term BPV with ABPM

The dynamic behavior of BP values over the 24-h period was first shown through use of intra-arterial

422 Curr Hypertens Rep (2012) 14:421–431


BP monitoring in ambulant subjects [37], which allowedidentification of both beat-by-beat and day-night BPvariations [37]. However, short-term BPV can also beestimated (although less precisely) from intermittent,non-invasive 24-h ABPM recordings, allowing calcula-tion of the standard deviation (SD) of average systolic,diastolic and mean arterial pressure values over the24-h period, or during the daytime and nighttime sub-periods [38]. However, the discontinuous sampling ofBP variations over the 24 h and the inclusion in thecalculation of 24-h BP SD of the degree of nocturnalBP fall (whose occurrence and magnitude carries afavorable prognostic value) have represented importantlimitations in the assessment of the prognostic relevanceof 24-h BPV through this approach [39, 40]. In order toovercome these difficulties, new parameters for quanti-fying short-term BPV over 24 h by excluding nighttimeBP reduction have been recently proposed. One is the“weighted” SD of the 24-h mean value, i.e., the averageof daytime and nighttime BP SD, each weighted for theduration of the day and night periods, respectively, inorder to exclude day-night BP changes from the quan-tification of overall 24-h SD [41]. Other methods arethe calculation of the "residual BPV" remaining afterexclusion of the slower components of the 24-h BPprofile through spectral analysis [42], and the average

of the absolute differences between consecutive meas-urements ("average real variability") [43]. These param-eters, which focus on short-term BP changes and arenot affected by the dipping phenomenon, have beenshown to be better predictors of organ damage andCV risk than the conventional 24-h SD [11, 41, 43].

Assessment of Long-Term BPV

The clinical relevance of visit-to-visit BPV, either inOBP or in average 24-h ABP values, has been recentlyshown, especially in predicting cerebrovascular events[14]. However, in the clinical setting obtaining BPmeasurements over a consistent number of visits toachieve a meaningful estimate of visit-to-visit BPV isusually difficult. An alternative approach consists in theassessment of long-term BPV from BP measures per-formed by patients at home using HBPM. It allowsobtaining day-by-day BP measures in a relatively shortperiod (several days), in fairly standardized conditions(the treatment regimen remains stable and significantphysiological changes are unlikely to occur) and without theinfluence of subject’s activity [44]. Thus, HBPM appearsmore appropriate for the long-term assessment of BPV andBP control than repeated OBP or ABP measurements.

Fig. 1 Different types of BPV, their determinants, and prognosticrelevance for CV and renal outcomes. AHT, antihypertensive treat-ment; BP, blood pressure; BPV, blood pressure variations; SOD, sub-clinical organ damage; CV, cardiovascular; ESRD, end-stage renal

disease; eGFR, estimated glomerular filtration rate; MA, microalbumi-nuria; MI, myocardial infarction. *Assessed in laboratory conditions;†cardiac, vascular and renal SOD; ‡BPV on a beat-by-beat basis hasnot been routinely measured in population studies

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Alterations in BPV in CKD: Mechanismsand Determinants

Hypertension and alterations in BPV are highly prevalent inCKD, significantly contributing to the progression to ESRDand to the already high CV risk associated with this condition.Subjects with CKD show marked alterations, disappearanceor even inversion of the circadian variation of BP [45]. Indeed,loss of the normal nocturnal decline in BP has been reportedwith a prevalence ≥50% at the earliest stages and up to >80 %in patients on hemodialysis (HD) [46]. Proposed mechanismsfor alterations of BPV in CKD have included an increasedcentral sympathetic drive (further enhanced by neurohormon-al activation arising from the failing kidney) [47] and reduc-tions in aortic and carotid baroreflexes (caused by uremia-related increased arterial calcification and stiffness) [48],among other contributing factors.

Subjects who have reached ESRD are characterized bymarked BP variations and alterations in circadian BPrhythm. The striking reductions in intravascular volumeimmediately after HD and its progressive increases through-out the interdialytic period determine an extremely variablebehavior of BP. Besides, increases in extracellular fluidassociated with low ultrafiltration rates/insufficient amountof dialysis have been found to be directly correlated with anincreased diurnal BPV and with a reduced nocturnal BP fall[49]. Conversely, the magnitude of change in BPV follow-ing a single HD session has been shown to be directlycorrelated with the change in body weight or the ultrafiltra-tion amount [50]. Aside from increasing BPV, volume ex-cess may also contribute to the extremely high prevalence ofnight hypertension and alterations in day-to-night BP pro-files observed in ESRD (i.e., 80 % of HD subjects may beclassified as being non-dippers or reverse dippers) [46].

Short-term BPV: Its Significance for CV and RenalPrognosis

Evidence has indicated that the adverse CV consequences ofhigh BP not only depend on absolute BP values, but also onBPV. Indeed, observational studies have demonstrated thatan increased short-term BPV is closely associated with thedevelopment, progression and severity of cardiac, vascularand renal organ damage [1–6, 51] and with an increased riskof CVevents and mortality [7–12, 42] independently addingto CV risk, over and above the contribution of elevatedmean BP levels. When focusing on the kidney, experimentalstudies in rats investigating the role of an elevated BPV inthe determination of renal organ damage by comparisonwith the classic risk factor of a high blood BP level haveidentified an increased short-term BPV to be a more criticaldeterminant for renal damage than mean BP levels [52].

However, no studies in humans have found a prevailingprognostic role of BPVover mean BP levels in determiningthe development or progression of renal dysfunction. Cross-sectional studies in non-treated essential hypertensives havefound an increased short-term BPV to be positively corre-lated with impaired renal function either when assessed withmicroalbuminuria [6], or by estimation of the glomerularfiltration rate (eGFR) [51], even after adjusting for baselinecharacteristics and ABPM parameters.

Nocturnal BP Levels and Reduced Nighttime BPDipping: its Relevance for CV and Renal Prognosis

When considering either general populations or hypertensivepatients only, longitudinal studies have demonstrated elevatednighttime BP to be prognostically superior to awake or24-h BP means in predicting CV morbidity and mortality[53–58], the development of CV events [53, 54, 59–61] aswell as overall mortality [53–55, 60, 62, 63]. This is notsurprising given the fact that a patient’s nocturnal BP level,without the pressor effects of physical activity, emotional stressand other environmental factors that are usually occurringduring the day, may be more reproducibly representative ofpatient’s true BP status. Also in subjects with CKD, BP levelsduring nighttime have been reported to bear the strongestprognostic value for mortality, fatal and nonfatal CV eventsand progression to ESRD compared to daytime or 24-h BP[64–67]. Consistent evidence from longitudinal studies hasshown absolute nighttime BP to be an independent predictorof the development and progression of renal disease, assessedeither with microalbuminuria or GFR worsening [68–71], upto progression to ESRD requiring initiation of HD [64, 66].

Not only the prognostic role of nighttime BP levels, butalso the relevance of a “non-dipping” pattern of BP has beenexplored in several studies. Subjects in whom a nocturnaldecrease in BP is blunted have been reported to have ahigher prevalence of subclinical organ damage [4] and anincreased risk of CVevents [72] and mortality [58], which iseven higher in patients in whom BP increases rather thandecreases at night (so called risers or “inverted dippers”).When focusing on the kidney, longitudinal studies havefound a non-dipping and/or a reverse dipping pattern ofnighttime BP to be an independent predictor of the devel-opment and progression of microalbuminuria [68, 70,73–75], an increase in proteinuria [76], decline in renalfunction (reductions in GFR and/or increase in creatininelevels) [46, 77–80], faster progression of CKD and poorrenal prognosis (i.e., progression to ESRD) [66, 81–84].

Although in some studies the association of non-dippingwith renal outcomes has lost significance after adjustmentfor common risk factors, most studies have provided evi-dence that the lack of a physiological BP decline during



nighttime may be a strong predictor of the development andprogression of renal disease in different settings (i.e., newlydiagnosed hypertension, treated hypertension, diabetes andCKD). Finally, most but not all cross-sectional studies havefound nocturnal BP levels and a non-dipping profile of BPto be associated with impaired renal function (assessedeither with microalbuminuria or eGFR) and with renal dam-age (severity of CKD and presence of ESRD), as recentlyshown in a systematic review of the relevant literature [85].

Long-Term BPV (Day By Day): its Relevance for CVand Renal Prognosis

Although most studies on the prognostic relevance of BPVhave focused on short-term BP changes assessed from24-h ABPM, it has been suggested that also an increasedday-by-day BPV identified by HBPM may significantly pre-dict the risk of CV events [86]. In the Ohasama study, anincreased day-by-day systolic HBP variability was indeedassociated with an increased risk of a composite of cardiacand stroke mortality. However, when these conditions wereseparately considered, HBP variability remained a significantpredictor of stroke mortality but not of cardiac mortality [13].More recently, evidence on the prognostic value of day-by-day HBP variability was provided in a cohort of adults fromthe general population in the frame of the Finn-Home Study[87]. After 7.8 years of follow-up, increasing levels ofmorning-evening and morning day-by-day HBP variabilitywere found to be significant and independent predictors ofCVevents. A recent cross-sectional analysis in a population ofnever-treated hypertensives showed an increased day-by-dayHBP variability to be associated with the severity of cardiac(i.e., left ventricular mass index), macrovascular (i.e., in-creased carotid intima-media thickness) and microvascular(i.e., urinary albumin/creatinine ratio) organ damage [88].Several studies have suggested that an increased day-by-dayHBP variability may be an important risk factor for the devel-opment and progression of diabetic nephropathy [89]. Indeed,a recent study in subjects with type 2 diabetes showed day-by-day HBP variability to be significantly associated with macro-albuminuria independently of respective mean BP levels andother known risk factors [90]. However, not all studies havefound an increased day-by-day HBP variability in associationwith decreased renal function (assessed with eGFR) [91] orwith an increased incidence of renal outcomes [92].

Visit-To-Visit BPV: its Relevance for CV and RenalPrognosis

Recent studies, mostly in treated hypertensives, have foundan increased visit-to-visit BPV within a given patient to be

predictive of cerebrovascular events [14, 93], acute myocar-dial infarction [94] and all-cause mortality independently ofmean BP levels [15]. Visit-to-visit BPV has also been foundto be associated with different types of subclinical organdamage: cardiac (i.e., diastolic dysfunction) [95], macro-vascular (increased intima-media thickness and stiffness)[96], microvascular (development of micro- and macroalbu-minuria, and renal vascular atherosclerosis) [97, 98], cere-bral (white matter hyperintensity volume and presence ofbrain infarctions) [99] and endothelial dysfunction [100].When it comes to the kidney, an increased visit-to-visitBPV has been found to be significantly associated withalbuminuria [97, 98], macroalbuminuria [98] and the sever-ity of CKD (as assessed through urinary albumin excretion)[101], independently adding to mean BP levels in predictingthe risk of development and progression of nephropathy.

Alterations in BPV in ESRD: their Relevance for CVPrognosis

Alterations in BPV in ESRD may be of prognostic rele-vance, as indicated by a prospective study in HD patientsin whom an increased BPV was shown to be an indepen-dent, significant predictor of all-cause mortality [102]. Pro-spective studies in HD patients have found elevatednocturnal BP levels to be independent predictors of CVmortality [65] and a non-dipping pattern of BP to be a potentpredictor of CV events and CV mortality [103]. Volumeoverload has been proposed as a major mechanism for thesealterations as it has been associated with elevated BP levels(especially at night) and significant increases in BPV. Sincethese alterations may further contribute to the already highCV risk in ESRD patients, considerable efforts should bemade to prevent large interdialytic weight gain in HDpatients, in addition to achieving BP control and stabilizingBPV with antihypertensive treatment. However, this is achallenging objective in HD patients because of the impor-tant alterations in the pharmacokinetics of antihypertensivedrugs (i.e., impaired excretion and dialyzability).

Short-Term BPV: Should it be a Targetof Antihypertensive Treatment for Prevention of CVand Renal Disease?

It has been suggested that an optimal antihypertensive treat-ment should reduce BP-related CV risk through reduction of24-h mean BP levels and reduction of 24-h BPV. Althoughevidence has consistently supported the analysis of BPfluctuations over time as a potential tool to improve thetherapeutic approach to hypertension and to assess the effi-cacy of antihypertensive treatment, a number of reasons



have until now prevented the introduction of BPV assess-ment in the routine clinical management of hypertension.There is still limited evidence from longitudinal outcomestudies on the ability of specific drug classes to reduce BPVindependently of mean BP reduction [22, 23], as well as thepossibility that a treatment-induced reduction in short-termBPV might also reduce the development/progression oforgan damage and the risk of CV events [23]. Experimentalstudies in rats have indicated a beneficial effect of specificdrug classes (i.e., calcium channel blockers, CCB) in reduc-ing BPV and preventing cardiac, renal and brain organdamage [104], suggesting plausible putative mechanismsfor these benefits (i.e., restoration of baroreflex sensitivity)[105, 106]. Although evidence from clinical studies inhumans is limited to consistently support the ability ofspecific drug classes to promote reductions in short-termBPV and to protect against organ damage and improveoutcome, recent studies have provided evidence in thisregard. A couple of studies showed that, compared withother antihypertensive drugs, CCB may significantly lowershort-term BPV independently of mean BP reductions [107,108]. A series of studies in subjects with CKD have foundsignificant reductions in short-term BPV after long-termtreatment with angiotensin receptor blockers [109–111]. Ofnote, these reductions in BPV were directly correlated withreductions in urinary protein excretion [109] and in meas-ures of CV remodeling (i.e., LVMI) [110, 111]. In essentialhypertensive patients, bedtime administration of the angio-tensin receptor blocker (ARB) valsartan has not only beeneffective in restoring nighttime dipping of BP, but also inreducing urinary albumin excretion [112]. Finally, a recentprospective study (median follow-up of 5.6 years) providedevidence that decreasing asleep BP may confer substantialreductions in the incidence of CV events and mortality,independently of changes in any other parameters of ABPM[113].

Should Long-Term BPV be a Therapeutic Targetof Antihypertensive Treatment for Prevention of CVand CKD?

An increase in the proportion of visits with BP control hasbeen shown to be accompanied by a progressive reductionin the risk of CV events independently of mean BP levelsduring treatment [114]. Although long-term BPV (especial-ly when assessed by HBPM) might be a practical tool toassess the efficacy of antihypertensive drugs on day-by-dayBPV, evidence that specific drug classes may reduce CVoutcome through their effects on long-term BPV is stilllimited. Only recently, a meta-analysis of several random-ized controlled trials showed that the differences betweenclasses of antihypertensive drugs in their effectiveness in

preventing stroke might be due to class effects on BPVindependently of effects on mean SBP [115]. However, amajor limitation of the study was that instead of consideringintra-individual BPV (i.e., visit-to-visit BP variations withinthe same subject), it considered inter-individual BPV inmost cases (i.e., BP variations at different times in indepen-dent groups of subjects), which cannot accurately reflect BPvariations from visit to visit. More recently, a post hocanalysis of the Anglo-Scandinavian Cardiac Outcomes TrialBlood Pressure Lowering Arm (ASCOT-BPLA) indicatedthat benefits of CCB in the prevention of CV events may bepartly attributed to the reduction in visit-to-visit BPV [14].A post hoc analysis of the J-CORE study provided evidencethat adding a CCB to an ARB may decrease day-by-dayHBP variability more effectively than a diuretic-ARB com-bination even in the absence of significant differences inmean HBP levels between regimens [116]. Contrastingly, apost-hoc analysis of the recently published European Laci-dipine Study on Atherosclerosis (ELSA study) found nosignificant differences between CCB and beta blockers intheir ability to reduce visit-to-visit BPV [117].

Nocturnal Hypertension and a Non-Dipping Patternof BP: Should They Be a Target of AntihypertensiveTreatment for Preventing Progression of Renal Disease?

Against the background of the evidence supporting the prog-nostic relevance of nocturnal hypertension and a non-dippingpattern of BP, the question of whether reducing nocturnal BPshould be a therapeutic target for reducing the developmentand progression of renal disease has been raised. The effects ofantihypertensive drugs on circadian BP profiles are differentdepending on the duration and mechanism of action, time ofdosing, concentration in the blood and patient conditions.Since insufficient BP control at night is often caused by lowblood drug concentrations, several strategies, such as shiftingthe timing of the antihypertensive drug administration (i.e.,taking drugs once daily before going bed rather than in themorning), taking the drugs twice daily (i.e., in the morningand before bed) or using long-acting antihypertensive drugsthat are effective over the 24 h (i.e., having a high trough/peakratio), have been proposed. A recent study in non-dipperpatients with CKD showed the efficacy of shifting the admin-istration of an antihypertensive drug from morning to eveningin restoring the normal circadian rhythm of BP in 87.5 % ofpatients, in decreasing nocturnal BP and in reducing protein-uria while avoiding intensification of the required therapy[76]. However, whether selective reduction of nocturnal BPor changing a patient from being a non-dipper to dipper can bea therapeutic target to reduce CV risk and prevent progressionof renal dysfunction in patients with CKD should still be betterdefined.



Conclusions

Consistent evidence has indicated that an increased BPV isassociated with the development, progression and severity ofcardiac, vascular and renal organ damage, and with an in-creased risk of CVevents and mortality, independently addingto CV risk, over and above the contribution of elevated meanBP levels. Either in the short or the long term, alterations inBPV have been shown to be independent predictors of devel-opment and progression of renal dysfunction, which is con-sidered a marker of a very high CV risk in hypertensivepatients. It has thus been suggested that in order to achievethe highest CV protection in hypertensive patients, especiallyin those with CKD, antihypertensive treatment should betargeted at normalizing 24-h BPV in addition to reducingabsolute 24-h BP levels. However, evidence is still limitedregarding the targets of BPV to achieve with antihyperten-sives. Moreover, little is known about the possibility thatspecific drug classes or combinations might lower BPV inde-pendently of mean BP reduction.

Recent studies have provided a valuable contribution tothe ongoing research on the management of BPV (either inthe short term or its day-by-day component), further sup-porting the possibility of including the assessment of thisparameter in everyday clinical practice. At the same time,some of these studies have allowed a better understanding ofwhich therapies might reduce the risk related to an increasedBPV in hypertension, suggesting plausible putative mecha-nisms for these benefits and indicating directions for futureresearch in this field. Overall, the data provided by prospec-tive studies in hypertension and in CKD emphasize theprognostic relevance of identifying altered day-to-night BPprofiles and of targeting BP-lowering strategies to theirnormalization in order to reduce CV morbidity and mortalityand to limit the progression of CKD. Since patients withCKD are characterized by frequent alterations in circadianBP profiles, it is clear that without the use of ABPM (whichallows assessment of nocturnal BP during sleep), the car-diovascular and/or renal risk of being non-dippers or night-time BP risers could not be assessed in a large proportion ofthem. Finally, assessment of long-term BPV, especially itsassessment on a day-by-day basis by means of HBPM, mayalso help the practicing physician to optimize antihyperten-sive treatment at every clinic visit, thus improving stabili-zation of BP levels in the long term.

It has to be emphasized, however, that in spite of allthe evidence presented in this article supporting the clin-ical relevance of BPV both for cardiovascular and renaloutcomes, a reduction in BPV cannot yet be recommen-ded as a target for treatment in daily clinical practice.This is because target BPV levels to achieve by treat-ment have not yet been defined, and because prospectiveoutcome studies are still needed to demonstrate that a

treatment–induced reduction in BPV is accompanied by acorresponding reduction in CV and renal events as wellas in mortality.

Disclosure No potential conflicts of interest relevant to this articlewere reported.

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blood pressure variability, cardiovascular risk and antihypertensive treatment

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