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Blood pressure is not a static parameter, but rather undergoes continuous fluctuations over time, as a result of the interaction between environmental and behavioural factors on one side and intrinsic cardiovascular regulatory mechanisms on the other side. Increased blood pressure variability (BPV) may indicate an impaired cardiovascular regulation and may represent a cardiovascular risk factor itself, having been associated with increased all-cause and cardiovascular mortality, stroke, coronary artery disease, heart failure, end-stage renal disease, and dementia incidence. Nonetheless, BPV was considered only a research issue in previous hypertension management guidelines, because the available evidence on its clinical relevance presents several gaps and is based on heterogeneous studies with limited standardization of methods for BPV assessment. The aim of this position paper, with contributions from members of the European Society of Hypertension Working Group on Blood Pressure Monitoring and Cardiovascular Variability and from a number of international experts, is to summarize the available evidence in the field of BPV assessment methodology and clinical applications and to provide practical indications on how to measure and interpret BPV in research and clinical settings based on currently available data. Pending issues and clinical and methodological recommendations supported by available evidence are also reported. The information provided by this paper should contribute to a better standardization of future studies on BPV, but should also provide clinicians with some indications on how BPV can be managed based on currently available data.

The present paper provides an update of previous recommendations on Home Blood Pressure Monitoring from the European Society of Hypertension (ESH) Working Group on Blood Pressure Monitoring and Cardiovascular Variability sequentially published in years 2000, 2008 and 2010. This update has taken into account new evidence in this field, including a recent statement by the American Heart association, as well as technological developments, which have occurred over the past 20 years. The present document has been developed by the same ESH Working Group with inputs from an international team of experts, and has been endorsed by the ESH. ispartof: JOURNAL OF HYPERTENSION vol:39 issue:9 pages:1742-1767 ispartof: location:Netherlands status: published

Hypertension control still remains a largely unmet challenge for public health systems. Despite the progress in blood pressure (BP) measurement techniques, and the availability of effective and safe antihypertensive drugs, a large number of hypertensive patients are not properly identified, and a significant proportion of those who receive antihypertensive treatment fail to achieve satisfactory control of their BP levels. It is thus not surprising that hypertension is still a major contributor to disease burden and disability worlwide, even in developed countries. This paper will address current challenges in hypertension management and potential strategies for an improvement in this field. In its first part relevant issues related to hypertension diagnosis will be addressed, in particular how to improve identification of sustained BP elevation and specific BP phenotypes such as white coat and masked hypertension trough the combined use of office and out-of-office BP monitoring techniques. In its second part focus will be on how to improve achievement of hypertension control in treated patients by optimization and simplification of medication regimens, including more efficient selection and titration of antihypertensive drugs and their combinations, aimed at achieving a more consistent 24hBP control; and by favoring a more active patients' and physicians' involvement in hypertension management also through BP telemonitoring and mobile health technologies.

Due to fast-paced technological advancements, digital health and telemedicine represent a promising and complex reality, with the potential to change the current management of hypertension and improve its outcomes. New types of health-related strategies are available, ranging from telemonitoring of blood pressure (BP) values to counseling for patients and decisional tools for physicians, thanks to the development of new technology. Even though the strength of available evidence is currently low due to the high heterogeneity of studies and of the proposed interventions, available data suggest a beneficial effect of digital health strategies on BP control and, more generally, on cardiovascular risk reduction. In addition, well-designed randomized controlled trials are needed to further investigate the real impact of these new strategies on clinical outcomes. Furthermore, due to consistent commercial interests in this field, there is a strong need for strict regulations to ensure a safe and secure implementation of this new reality in clinical care.

Blood pressure (BP) is one of the most dynamic physiologic variables that is routinely measured in clinical practice and is characterized by continuous and significant changes beat-to-beat, over 24 h, day-to-day, and visit-to-visit. Under physiological conditions, these BP variations largely represent a response to environmental stimulations and challenges of daily life aimed at maintaining so-called cardiovascular “homeostasis”. However, sustained increases in blood pressure variability (BPV) may also reflect alterations in cardiovascular regulatory mechanisms or underlying pathological conditions and may represent a source of damage to the cardiovascular system. The clinical significance and prognostic implications of these BP variations have been demonstrated by a series of clinical and population studies conducted in recent years, in which increasing BPV has been associated with a higher risk of subclinical organ damage, cardiovascular events, and cardiovascular and all-cause mortality, independent of elevated average BP values. This paper will review the available evidence on the current definitions, classification, and mechanisms responsible for different types of BPV by focusing on their relevance to cardiovascular homeostasis and cardiovascular disease.

Background The band 9p21.3 contains an established genomic risk zone for cardiovascular disease (CVD). Since the initial 2007 Wellcome Trust Case Control Consortium study (WTCCC), the increased CVD risk associated with 9p21.3 has been confirmed by multiple studies in different continents. However, many years later there was still no confirmed report of a corresponding association of 9p21.3 with hypertension, a major CV risk factor, nor with blood pressure (BP). Theory In this contribution, we review the bipartite haplotype structure of the 9p21.3 risk locus: one block is devoid of protein-coding genes but contains the lead CVD risk SNPs, while the other block contains the first exon and regulatory DNA of the gene for the cell cycle inhibitor p15. We consider how findings from molecular biology offer possibilities of an involvement of p15 in hypertension etiology, with expression of the p15 gene modulated by genetic variation from within the 9p21.3 risk locus. Results We present original results from a Colombian study revealing moderate but persistent association signals for BP and hypertension within the classic 9p21.3 CVD risk locus. These SNPs are mostly confined to a ‘hypertension island’ that spans less than 60 ​kb and coincides with the p15 haplotype block. We find confirmation in data originating from much larger, recent European BP studies, albeit with opposite effect directions. Conclusion Although more work will be needed to elucidate possible mechanisms, previous findings and new data prompt reconsidering the question of how variation in 9p21.3 might influence hypertension components of cardiovascular risk., Graphical abstract Schematic depiction of the main observation from association data presented or discussed in this article. Two adjacent haplotype blocks characterize the 9p21.3 cardiovascular risk locus: left, the block or island containing the first part of the p15 gene and its well-studied promoter, characterized by elevated associations (red) with blood pressure (DBP, SBP) and/or hypertension in Colombian and European studies, and right, the block containing lead cardiovascular risk-associated SNPs such as rs1333049 and rs1333050 (blue) but containing no protein-coding genes.Image 1

A series of studies in the last decades have indicated that the risk of cardiovascular complications may not only depend on the magnitude of the elevation of average BP levels per se but also on an increased blood pressure variability. This concept has been supported by several reports, showing that increasing values of blood pressure variability either in the short term (24 h), in the midterm (day-by-day), or in the long term (visit-to-visit), may contribute to cardiovascular risk prediction over and above the impact of average BP levels. This chapter will focus on the day-by-day variations in BP values self-measured at home by patients, by addressing their mechanisms, the methodological aspects that should be considered for their assessment based on home BP measurements as well as their clinical relevance for cardiovascular prognosis. We will also address some yet pending issues which still make application of day-by-day Home Blood Pressure (HBP) variability difficult in daily practice. These include the additional contribution given by HBP variability to risk prediction, on top of what is offered by average HBP levels, and whether antihypertensive treatment strategies should be targeted at reducing not only average BP levels but also the degree of day-by-day blood pressure variability in order to optimize cardiovascular protection.

Blood pressure telemonitoring (BPT) allows remote transmission of patients’ BP values from their home or the community setting, to the doctor’s office or hospital. Evidence from several clinical trials has supported the efficacy of BPT in improving patients’ compliance and adherence to antihypertensive treatment and in achieving hypertension control, with the consequent possibility to improve cardiovascular protection by preventing the adverse consequences associated with elevated BP levels. Until a few years ago, computer-tailored solutions were the main approach to BPT. In recent years, however, the widespread use of smartphone technologies along with the development of related applications for BP monitoring and remote transmission, have made also possible to implement and deliver BPT via mobile phones (mHealth). This chapter will review the clinical relevance of BPT, either when using computer-based or m-health strategies, addressing important methodological aspects for its clinical application, the evidence on their effects on BP levels and achievement of hypertension control, as well as their advantages and limitations for the overall management and follow-up of hypertension and the yet pending issues to be addressed in future studies.

During blood pressure (BP) measurement, the recommended positioning of the cuff bladder center is directly above the brachial artery. We investigated the relevance of incorrect cuff positioning during (1) auscultatory measurement with an appropriate or improperly small cuff and (2) oscillometric measurement with a wide-range cuff designed to guarantee accurate measurements regardless of position. In subjects with wide BP and arm circumference ranges, (1) auscultatory BP was repeatedly measured with a properly positioned cuff (reference) and, simultaneously, with an identical cuff placed on the other arm in either a correct or an incorrect position (test). The measurements were performed with a properly sized (N=57) or an improperly small cuff (N=33). (2) Auscultatory measurements obtained with a properly positioned and sized cuff were compared with oscillometric measurements obtained with a specially designed wide-range cuff (Omron IntelliWrap) placed on the contralateral arm either in a correct or an incorrect position. Auscultatory BP measures were unaffected by incorrect positioning of a properly sized cuff, whereas with undercuffing, BP was overestimated with the cuff displaced by 90° laterally (systolic/diastolic BP differences: 4.9±4.6/4.0±4.6 mm Hg, P

Background Obtaining 24‐hour ambulatory blood pressure (BP) is recommended for the detection of masked or white‐coat hypertension. Our objective was to determine whether the magnitude of the difference between ambulatory and clinic BPs has prognostic implications. Methods and Results We included 610 participants of the AASK (African American Study of Kidney Disease and Hypertension) Cohort Study who had clinic and ambulatory BPs performed in close proximity in time. We used Cox models to determine the association between the absolute systolic BP (SBP) difference between clinic and awake ambulatory BPs (primary predictor) and death and end‐stage renal disease. Of 610 AASK Cohort Study participants, 200 (32.8%) died during a median follow‐up of 9.9 years; 178 (29.2%) developed end‐stage renal disease. There was a U‐shaped association between the clinic and ambulatory SBP difference with risk of death, but not end‐stage renal disease. A 5– to, See Editorial Parati et al

A large body of evidence has consistently supported the relationship between blood pressure (BP) levels and the risk of cardiovascular complications. A series of studies in the last decades have indicated that this risk may not only depend on the magnitude of the elevation of average BP levels per se but also on the presence of other associated conditions such as increased BP variability (BPV) or an increased BP load. This concept has been supported by a series of studies, showing that increasing values of BPV either in the short term (24 h), in the mid-term (day by day), or in the long term (visit to visit) may predict development, progression, and severity of cardiac, vascular, and renal organ damage, as well as cardiovascular events and mortality. Some evidence has also been provided showing that an increased BP load, i.e., the percentage of readings above threshold values set for daytime and nighttime on 24h ambulatory BP monitoring (ABPM), is associated with indices of subclinical organ damage and cardiovascular outcomes. Whether BPV and BP load might represent useful parameters complementing the quantification of average BP levels in clinical practice is still a matter of active discussion, however. In its first part, this chapter will review the currently available data on BPV, including its mechanisms, the methodological aspects that should be considered for its assessment, and its relevance and significance for cardiovascular prognosis as well as its potential for application in clinical practice. In its second part, it will address the concept of BP load, discussing not only methodological issues related to its assessment but also its clinical relevance and whether a proper interpretation of ABPM should include its quantification in addition to average BP values and BPV.

Introduction Masked uncontrolled hypertension (MUCH) carries an increased risk of cardiovascular (CV) complications and can be identified through combined use of office (O) and ambulatory (A) blood pressure (BP) monitoring (M) in treated patients. However, it is still debated whether the information carried by ABPM should be considered for MUCH management. Aim of the MASked-unconTrolled hypERtension management based on OBP or on ambulatory blood pressure measurement (MASTER) Study is to assess the impact on outcome of MUCH management based on OBPM or ABPM. Methods and analysis MASTER is a 4-year prospective, randomised, open-label, blinded-endpoint investigation. A total of 1240 treated hypertensive patients from about 40 secondary care clinical centres worldwide will be included -upon confirming presence of MUCH (repeated on treatment OBP

Imprecise blood pressure (BP) measurement may be responsible for inappropriate diagnosis and classification of hypertension, resulting in either excessive or insufficient use of antihypertensive drugs. On the background of the enormous impact of hypertension in terms of global disease burden, an accurate measurement and classification of BP levels becomes a fundamental step for the appropriate management of hypertensive patients. This chapter will provide an overview of the different methodologies currently available for BP measurement in the medical office, such as conventional office blood pressure (OBP) readings and unattended automated office blood pressure measurements (AOBP). It will also address techniques for BP measurement out of the doctor’s office such as 24 h ambulatory blood pressure monitoring (ABPM) and home blood pressure monitoring (HBPM), giving also practical recommendations for their implementation in clinical practice, based on current hypertension Guidelines. The chapter will also review the current definitions and classification of BP levels based on different BP measurement techniques, the abnormalities in 24 h BP patterns that can be identified through ABPM, and the different BP phenotypes that result from the discrepancies between office and out- of- office BP measurement techniques when used in combination (i.e. white coat hypertension and masked hypertension).

Context: Epidemiological studies have shown a progressive increase in insulin resistance (IR) accompanying body weight gain and blood pressure (BP) increase. This has led to the consideration that hemodynamic effects of IR might depend on its relationship with body mass index (BMI) and BP. Objective: The aim of our study was to determine whether IR is associated with changes in hemodynamic indices of cardiovascular function across different categories of BMI (normal weight, overweight, and obese), and BP levels (normal, high normal, and hypertension). Design, Setting and Participants: This was a cross-sectional study conducted in a population sample of nondiabetic individuals (n = 731). Measures: Insulin resistance was evaluated with the homeostasis model assessment of insulin resistance (HOMA) and subjects were classified into quartiles according to HOMA index values. Synchronized beat-to-beat recordings of stroke volume (impedance cardiography) and R-R interval, along with repeated auscultatory BP measurements were performed. Derived hemodynamic parameters were computed and averaged. Results: Analysis of covariance adjusting for confounders showed significant differences for most hemodynamic parameters among different quartiles of HOMA index both in the general population and within each BMI and BP category. Overall, increasing values of HOMA index were associated with significantly higher BP; and reduced R-R interval, stroke index, cardiac index, pre-ejection period and left ventricular ejection time (P < .01) across different categories of BMI and BP. Conclusions: These findings suggest that even small increases in HOMA index (not necessarily in the range to define IR) may induce significant changes on indices of cardiovascular function even in normal-weight and normotensive subjects, emphasizing the importance of IR at an early stage of the cardiovascular risk continuum.

Office blood pressure measurement has been the basis for hypertension evaluation for almost a century. However, the evaluation of blood pressure out of the office using ambulatory or self-home monitoring is now strongly recommended for the accurate diagnosis in many, if not all, cases with suspected hypertension. Moreover, there is evidence that the variability of blood pressure might offer prognostic information that is independent of the average blood pressure level. Recently, advancement in technology has provided noninvasive evaluation of central (aortic) blood pressure, which might have attributes that are additive to the conventional brachial blood pressure measurement. This position statement, developed by international experts, deals with key research and practical issues in regard to peripheral blood pressure measurement (office, home, and ambulatory), blood pressure variability, and central blood pressure measurement. The objective is to present current achievements, identify gaps in knowledge and issues concerning clinical application, and present relevant research questions and directions to investigators and manufacturers for future research and development (primary goal).

Obstructive sleep apnea syndrome (OSAS), combining nighttime occurring intermittent obstruction of upper airways with daytime somnolence, is associated with impairment in important mechanisms of cardiovascular regulation, in particular with neural and reflex mechanisms involved in blood pressure (BP) control. The resultant sympathetic activation and the associated metabolic and humoral responses lead to important autonomic and hemodynamic changes (vasoconstriction, fluid retention, elevated blood pressure and blood pressure variability, elevated heart rate, and reduced heart rate variability), which are not only present during the apneic episodes occurring at night but also during daytime wakefulness. The presence of all these conditions, the magnitude of which is directly associated to the severity of OSAS, not only promotes future development of hypertension but also makes hypertension occurring in OSAS more severe and resistant to antihypertensive treatment and associated with profound alterations in day-to-night BP changes. The evidence mentioned above highlights the relevance of OSAS as a risk condition not only for arterial hypertension but also for other cardiovascular diseases. This chapter is aimed at reviewing: 1. The effects of OSAS on different mechanisms involved in integrated cardiovascular modulation (2) The resultant autonomic and hemodynamic responses to these alterations 2. The epidemiological evidence supporting the association of elevated BP with OSAS 3. The prognostic significance of OSAS-related hypertension 4. The diagnostic approach to OSAS-related hypertension 5. Finally, the role of pharmacological and non-pharmacological strategies on OSAS-related hypertension with emphasis on CPAP (i.e., which is known to be effective in reducing the sympathetic nervous system overdrive; a major contributing mechanism for OSAS-related alterations in BP regulation) and whether it may promote achievement of BP control and stabilization of BP levels for improving cardiovascular morbidity and mortality in OSAS patients

An impaired renal function has been found associated with very high cardiovascular (CV) risk, especially in subjects with type 2 diabetes. Microalbuminuria is a sensitive early marker of renal damage, often preceding the more advanced stages of diabetic nephropathy. Consistent evidence has been provided that any degree of quantifiable albuminuria, even in the range of normoalbuminuria, is a significant predictor of CV events and progression to end-stage renal disease. This is of particular relevance in subjects with type 2 diabetes in whom the prevalence of microalbuminuria may be as high as 50%. This has motivated the search for novel, yet modifiable risk factors the correction of which may contribute to prevention of albuminuria development and of renal impairment progression in patients with type 2 diabetes, aimed at further reducing the overall CV risk profile in these patients. One of these proposed novel risk factors is an increase in blood pressure variability (BPV). This suggestion is supported by a series of studies, carried out either in diabetic and in nondiabetic populations, which have provided evidence that an increased BPV, in addition to increased average BP levels, may be an independent predictor not only of CV events and mortality but also of development and progression of renal disease. The purpose of the present paper is to provide a critical review of the evidence exploring the relationship between BPV and renal dysfunction with particular emphasis on the relationship between visit-to-visit BPV and urinary albumin excretion variability.

RESUMEN: Introducción: el síndrome metabólico (SM) es una condición clínica que aumenta el riesgo de enfermedad cardiovascular y se relaciona con resistencia a la insulina (RI). Aunque los consensos establecen la necesidad de puntos de corte específicos del perímetro de la cintura (PC) para cada país, con el fin de identificar sujetos con SM, en Colombia no han sido definidos. Objetivo: definir los puntos de corte del PC en hombres y en mujeres que mejor discriminan la presencia de RI, establecer la prevalencia de SM y verificar la relación entre el PC y RI. Materiales y Métodos: en el contexto del estudio Diagnóstico del Riesgo Cardiovascular Global, Medellín 2007-2008, se realizó una evaluación clínica, antropométrica y de laboratorio. Con el índice de resistencia a la insulina HOMA (IR-HOMA) se definió la presencia de RI a partir del percentil 75. Se construyeron curvas de las características operativas del receptor (COR), se obtuvo el área bajo la curva (AUC) para cada sexo y se usó el índice de Youden para establecer el PC que mejor discriminaba la presencia de RI. Resultados: se incluyeron 800 sujetos, de los cuales el 44,8% fueron hombres, con un promedio de edad de 50,3±12,1 e índice de masa corporal (IMC) de 26,1±4,7. Los sujetos con RI tuvieron mayor PC, triglicéridos y presión arterial, además, menor colesterol HDL que aquellos sin RI. Los valores que mejor discriminan la presencia de RI fueron 92 cm en hombres (sensibilidad 82,28%; especificidad 70,14%) y 84 cm en mujeres (sensibilidad 78,15%; especificidad 73,98%) (índice de Youden de 0,52 en ambos sexos). Para los hombres y mujeres el AUC fue 0,828 (IC 95% 0,780-0,876) y 0,815 (IC 95% 0,770-0,859), respectivamente, valor de p< 0,001. Se encontró correlación entre el PC e IR-HOMA (ρ=0,65 en los hombres y ρ=0,62 en las mujeres) y una prevalencia del SM del 44,9%. Conclusión: los valores de PC que mejor discriminaron la presencia de RI son 92 cm para hombres y 84 cm para mujeres. Este criterio podría ser utilizado para identificar sujetos con SM a nivel poblacional. ABSTRACT: Introduction: the metabolic syndrome (MS) is a clinical condition that increases the risk of cardiovascular disease and is associated with insulin resistance (IR). Although consensus establish the need of specific cut points of waist circumference (WC) for each country in order to identify subjects with MS, these have not been defined in Colombia. Objective: to define the WC cut points in men and women that best discriminate the presence of IR, to establish the prevalence of MS and verify the relation between WC and IR. Material and methods: in the context of the Diagnosis of the Global Cardiovascular Risk study, Medellin 2007-2008, we conducted an anthropometric and laboratory clinical evaluation. With the HOMA insulin resistance (HOMA-IR) index, we defined the presence of IR starting from the 75th percentile. Curves of the receiver operating characteristics (ROC) were made and the area under the curve (AUC) for each sex was obtained and the Youden index was used to establish the WC that best discriminated the presence of IR. Results: 800 subjects were included, of whom 44.8% were male, with a mean age of 50.3 ± 12.1 years and body mass index (BMI) of 26.1 ± 4.7. Subjects with IR had higher WC, triglycerides and blood pressure and also lower HDL cholesterol than those without IR. The values that best discriminate the presence of IR were 92 cm in men (sensitivity 82.28%, specificity 70.14%) and 84 cm in women (sensitivity 78.15%, specificity 73.98%) (Youden index of 0 , 52 in both sexes). For men and women, the AUC was 0.828 (95% CI 0.780-0.876) and 0.815 (95% CI 0.770 to 0.859), respectively, p

Blood pressure (BP) is characterized by marked fl uctuations occurring within the 24 h as a result of complex interactions between behavioral, environmental, humoral, and neural central or refl ex infl uences. Signifi cant BP variations also occur over more prolonged periods of time (i.e. between days, weeks, months, seasons and even years), not as a random phenomenon but as a result of several interacting factors yet not completely identifi ed. Depending on the method and time interval considered for measurement, the clinical signifi cance and prognostic implications of different types of BP variability (BPV) may substantially differ. Either in the short or in the long term, BPV has been associated with development, progression and severity of cardiac, vascular and renal organ damage and with an increased risk of cardiovascular events and mortality, independently adding to cardiovascular risk, over and above the contribution of elevated mean BP levels. The present paper provides a review on the main methods currently employed for assessment of BPV as well as on the mechanisms, clinical interpretation and prognostic signifi cance of different types of BPV, addressing the question on whether BPV should be a target for antihypertensive treatment for the current prevention of cardiovascular disease.

Blood pressure (BP) has a well-documented, continuous relationship with cardiovascular risk,1 and hypertension has a huge impact at population level in terms of cardiovascular complications and mortality.2 On the other hand, BP reduction in hypertensive subjects is easily achievable and provides dose-dependent prognostic benefits.3 While evidence from large-scale trials represents the backbone for clinical decisions, physicians must strive to achieve a personalized approach to disease management in individual subjects, including those with hypertension and cardiovascular diseases. Indeed, current use of terms such as personalized or precision medicine refers to patients’ care guided by individual molecular characteristics combined with up-to-date diagnostic methods. Specifically, when considering hypertension management, it has been proposed that the intensity of BP lowering should be personalized according to individual cardiovascular risk profile, meaning that (1) prompt BP control should mainly be achieved in high-risk patients; and (2) achievement of lower BP levels may be beneficial in subjects at higher cardiovascular risk. Evidence is available that in high-risk individuals, absolute benefits of treatment are greatest, and pharmacological treatment is more cost-effective.4 On the other hand, when targeting high-risk hypertensive subjects, the large reduction of absolute cardiovascular risk obtained by treatment is accompanied by a considerable residual risk. The latter represents the excess of risk due to the presence of irreversible organ damage, which persists even after achieving optimal control of BP and other risk factors.5 On the contrary, an effective BP reduction by treatment obtained earlier in the clinical history of hypertension, that is in still low-risk individuals, leaves much less residual risk and, thus, offers more solid lifelong cardiovascular protection.5 This kind of reasoning supports the importance of achieving effective and early BP control also in subjects with mild–moderate BP elevations and low cardiovascular risk. Whether lower BP targets are justified …

See related article, pp 42–50 Epidemiological data indicating that the linear relationship between blood pressure (BP) and cardiovascular outcomes continues even below the traditional thresholds defining hypertension1 have led to the hypothesis that in high-risk patients, in whom small relative risk reductions translate into large absolute benefits, achieving BP values below lower thresholds might be clinically useful. The results of the few intervention studies specifically designed to provide an answer to the long debated question on how low BP should be attained in patients at high cardiovascular risk were not sufficiently consistent to support any solid recommendation in this regard, however.2–6 With the recent publication of the SPRINT (Systolic Blood Pressure Intervention Trial), it seemed that strong evidence in favor of lowering systolic BP

Blood pressure (BP) is characterized by high variability, including changes beat-to-beat (very short term), within 24 hours (short term), from day to day (midterm), and between visits spaced by weeks, months, seasons, and even years (long term). These variations can be estimated by means of continuous beat-to-beat BP recordings, repeated conventional office BP measures, 24-hour ambulatory BP monitoring (ABPM), or home BP monitoring (HBPM) over longer time windows (Table). A main advantage of ABPM over other BP measurement techniques is represented by its ability to track BP changes occurring in daily life conditions and during 24 hours, thus allowing assessment of overall BP variability (BPV) as well as identification of its specific components, such as nocturnal hypertension and altered day-to-night BP profiles (ie, morning BP rise, nondipping pattern of BP) which become manifest early in the course of chronic kidney disease (CKD). These alterations are even more significant in subjects with end-stage renal disease (ESRD) mainly, but not exclusively, because of the marked reduction in intravascular volume immediately after hemodialysis followed by the progressive increase in volemia throughout the interdialytic period,2 combined with an enhanced sympathetic activity. The higher frequency of alterations in 24-hour BP profiles and BPV in subjects with CKD and in those with ESRD not only makes a proper assessment and achievement of BP control more difficult in these subjects but may be prognostically relevant on the background of the evidence from longitudinal and observational studies indicating that increased BPV may predict the development of cardiovascular and renal disease, over and above the contribution of elevated mean BP levels per se3–11 (Figure 1). The purpose of this review is to address the currently available evidence on the role of ABPM and HBPM for the assessment and management of alterations in circadian BP profiles …

Hypertension is highly prevalent in chronic kidney disease (CKD), particularly in patients with end-stage renal disease (ESRD) receiving hemodialysis.1,2 The identification and treatment of hypertension in CKD has to face peculiar problems because of the marked alterations in 24-hour blood pressure (BP) profile, in particular of a reduced BP dipping at night, and the high prevalence of specific hypertension phenotypes, such as white coat (WCH) and masked hypertension (MH). Moreover, the ebb and flow of fluid volume in hemodialysis patients makes a proper assessment and achievement of BP control even more difficult. Although conventional BP measurements (CBP), performed in the office or in the dialysis unit by healthcare personnel, are currently recommended and applied for the diagnosis and management of hypertension in patients with CKD, including those on dialysis, these metrics are intrinsically inaccurate.3,4 CBP measurements are known to fail providing reliable estimates of the actual BP burden in several clinical conditions, and this is even more so in CKD and in hemodialysis patients. Thus, in addition to CBP measurements, proper assessment and management of hypertension in these patients should be ideally based also on out-of-office BP measurements, including ambulatory BP monitoring (ABPM) and home BP monitoring (HBPM), as acknowledged by a consensus document by the American Society of Hypertension and the American Society of Nephrology.5 In this article, we highlight the advantages and disadvantages of out-of-office BP monitoring for the management of arterial hypertension in these conditions, based on a thorough literature search through classical engines, such as Pubmed and Web of Science, supplemented by the authors' own expertise. The thresholds to define hypertension and BP targets for antihypertensive treatment in CKD patients are debated.6,7 The recommendation to lower office BP to

easonal variations in cardiovascular morbidity andmortality show a winter peak and summer nadir, asreported since decades across different latitudes,ethnic groups and age strata. Mortality excess in wintermonths is mostly related to cardiovascular events includingacute myocardial infarction, sudden death, stroke andpulmonary thromboembolism [1–3]. In a landmark studybasedon300000cardiovasculardeathsfromtheCanadianMortality Database, Sheth et al. [4] observed a 19 and 20%increase in mortality, respectively, from acute myocardialinfarctionandstroke,inJanuarycomparedwithSeptember.In a community-based study carried out in Minnesota, USAfrom 1979 to 2002, a 17% increase in sudden cardiac deathwas found in winter compared with summer [5]. Theassociation between cold weather and sudden death wassimilar over years, across age and sex groups and wasstronger for individuals without a previous history ofcoronary heart disease. Available data are mostly derivedfrom countries exposed to cold/temperate climates charac-terized by large variations in seasonal temperature. Similarfindings, however, have been also reported by studiesperformed in countries with smaller variations in environ-mental temperature. In a population of almost 1 millionpersons in Israel, mortality from ischemic heart disease andstroke in men was, respectively, 51 and 48% higher in mid-winter than in mid-summer; the corresponding figures inwomen were 48 and 40%, respectively [6]. Seasonal vari-ations have been also reported for nontraumatic rupture ofthoracic and abdominal aortic aneurysms [7].Exposure to winter weather conditions has been hypo-thesized to induce physiological and clinical changesincluding sympathetic activation, hemoconcentration,hypercoagulability, increase in plasma lipids and ininfections rate that, overall, may increase the incidenceof cardiovascular diseases [8,9]. As a direct effect of coldweather on the cardiovascular system, reflex coronary andsystemic vasoconstriction may occur. Platelet activationmay take place during viral infections; increased plateletstickiness and thrombus formation may provide a rationalefor the association between ischemic heart disease, strokeand influenza. Short-term and long-term effects of coldexposure on blood pressure (BP) have also been consist-entlydemonstratedinbothnormotensiveandhypertensiveindividuals. Thus, weather-related increments in BP areseen as major determinants of cardiovascular morbidityexcess in the cold season.TheseseasonalBPfluctuationsrepresent oneofthelongterm components of the variations that characterize BPbehavior in daily life. BP variability is indeed a dynamicand complex phenomenon including short-term andlong-term fluctuations as a result of intricate interactionsbetween behavioral, humoral and neural central or reflexinfluences. Although often overlooked, also environmentalfactors may importantly contribute to BP variations, asthey may potentially influence physiological mechanismsinvolved in BP regulation. Particularly, seasonal climaticchanges have been reported to be associated with BPvariations in humans, SBP and DBP levels presentingsignificant increases during winter months [10,11].Seasonal influences on BP were first described in theearly1960sbyRose[10],whoanalyzedBPmeasurementsin56 middle-aged men affected by ischemic heart diseaseduring a 1–3 years follow-up period and found a clearseasonal trend, with a peak in spring and a trough in latesummer. Additional evidence on this phenomenon hasbeen provided by large population studies including bothnormotensive and hypertensive individuals, showing thatseasonal BP changes are not only limited to conventionalBP measurements performed in the clinic but also affectout-of-office BP levels. Either when considering clinic BPvalues, the average of self-BP measurements performed byindividuals at home or the mean of the 24-h BP valuescollected by ambulatory BP monitoring (ABPM), BP levelshave been reported to be lower during summer and higherduring winter [12]. In the last decades, studies performed indifferent settings (i.e. clinical trials, general population

La cardiografía de impendancia (CGI) representa un método no invasivo para la evaluación del estado hemodinámico latido a latido. Aunque se introdujo por primera vez hace más de 40 años, la CGI ha mostrado un resurgimiento en la última década, a partir de una serie de estudios clínicos que han demostrado su precisión en la estimación del volumen latido, tanto contra el “gold-standard“invasivo (termodilución), como contra los métodos de referencia no invasivos (ecocardiografía). Diversos estudios demuestran la utilidad de esta técnica en el manejo del paciente con falla cardíaca y en el enfoque diagnóstico y terapéutico de la hipertensión arterial, por lo cual constituyen actualmente dos de las aplicaciones clínicas más importantes de la CGI. En falla cardiaca, los cambios en el volumen de líquido del tórax y del gasto cardíaco evaluados por CGI, han demostrado ser predictores de descompensación aguda, incluso semanas antes del inicio de la sintomatología respiratoria; además, permiten identificar el origen cardiogénico o respiratorio de la disnea cuando el examen físico y los demás paraclínicos no son concluyentes. En los pacientes con hipertensión arterial no controlada o resistente, la CGI permite realizar una mejor caracterización del fenotipo hipertensivo y elegir la estrategia farmacológica más específica para intervenir la alteración hemodinámica predominante (resistencia vascular vs. gasto cardiaco elevado). En este artículo se realiza una revisión de los principios biofísicos de la CGI y su utilidad en la evaluación no invasiva del estado hemodinámico, así como una evaluación crítica de la literatura que da soporte a su aplicación clínica en el tratamiento de la falla cardíaca y la hipertensión arterial.Impedance cardiography (ICG) represents a non-invasive method for hemodynamic assessment in a beat-to-beat basis. Since its introduction more than forty years ago, a renewed interest in the use of this technique during the last decade has been noticed, mainly as a result of a series of clinical studies showing its precision in the estimation of stroke volume either against invasive gold standard (i.e. thermodilution) or against non-invasive reference methods (i.e. echocardiography). On the other hand, ICG has demonstrated to be useful for the management of heart failure patients and for the diagnostic and therapeutic approach to hypertension, which currently constitute two of the major applications of ICG. In heart failure patients, changes in thoracic fluid content and cardiac output tracked by ICG have shown to be predictors of acute decompensation even weeks before respiratory symptoms appear; also allowing identification of a cardiac vs. respiratory origin of dyspnea when physical examination and laboratory tests are not conclusive. In the particular case of patients with uncontrolled or severe hypertension, ICG makes possible a better characterization of hypertensive phenotype leading to a more specific choice of pharmacological agents to treat the primary hemodynamic alteration (i.e elevated peripheral resistance vs. elevated cardiac output). The present review, provides a review of the biophysical principles of ICG and its precision in measuring stroke volume and present a critical assessment of the literature supporting its clinical application in the management of heart failure and arterial hypertension

European guidelines recommend that treating patients with hypertension to blood pressure (BP) goal is an important target for cardiovascular (CV) risk reduction. However, office BP may be a suboptimal target, given its limitations. Indeed, there is evidence that 24-h ambulatory BP monitoring (ABPM) parameters may score better in this regard, representing more accurate predictors of CV risk. In particular, mean 24-h BP and BP variability both correlate closely with hypertension end-organ damage and rate of CV events, which suggests that antihypertensive therapy should provide smooth BP control over the full 24-h dosing interval. The use of ABPM has demonstrated that fixed-dose combination therapy, comprising agents with complementary mechanisms of action, may overcome the challenge of suboptimal BP control by providing improvements in antihypertensive efficacy and tolerability throughout the 24-h period. Olmesartan/amlodipine is one of the latest combination therapies to be approved, and a number of large clinical trials have demonstrated the efficacy and tolerability of this combination in patients with mild-to-severe hypertension. Furthermore, recent ABPM studies of olmesartan/amlodipine-based treatment algorithms have shown the satisfactory 24-h antihypertensive efficacy of this fixed-dose combination. This review provides an overview of recent clinical data on the efficacy and tolerability of fixed-dose olmesartan/amlodipine combination therapy for the treatment of mild-to-severe hypertension, with a focus on sustained 24-h BP control.

Introduction In this issue of the Journal of Hypertension, an article by Haider et al. [1] provides evidence on the possibility to apply a respiratory training technique, based on intermittent respiration of a gas mixture exposing patients to normobaric hypoxia, in the nonpharmacological treatment of patients with chronic obstructive pulmonary disease (COPD). These patients are characterized by a low ventilatory drive to carbon dioxide and thus are at increased risk of developing hypercapnia, hypoxemia at night and elevated pulmonary artery pressure. An intervention aimed at improving their cardiorespiratory regulation would thus be welcome. The approach proposed by the authors, termed interval hypoxic training (IHT), was originally developed in the former Soviet Union in the 1990s, after which time it has been largely overlooked until recently. According to the hypothesis made by Haider et al., IHT may represent an alternative or supplementary form of rehabilitation, besides the traditional physical training, for COPD patients. In patients with chronic pulmonary disease, in whom the same investigators demonstrated the possibility to obtain favorable results with regular performance of a slow breathing exercise [2], the conventional training of respiratory muscles has worthy but limited results [1]. According to the data obtained by Haider et al., intermittent breathing of hypoxic gas mixtures could offer a better outcome in terms of cardiovascular regulation. Hereafter, a brief description of this technique and of the putative mechanisms involved in its effects is provided for the nonfamiliar reader.

Parati, Gianfranco, Juan Eugenio Ochoa, Camilla Torlasco, Paolo Salvi, Carolina Lombardi, and Grzegorz Bilo. Aging, high altitude, and blood pressure: A complex relationship. High Alt Biol Med 16:97-109, 2015.--Both aging and high altitude exposure may induce important changes in BP regulation, leading to significant increases in BP levels. By inducing atherosclerotic changes, stiffening of large arteries, renal dysfunction, and arterial baroreflex impairment, advancing age may induce progressive increases in systolic BP levels, promoting development and progression of arterial hypertension. It is also known, although mainly from studies in young or middle-aged subjects, that exposure to high altitude may influence different mechanisms involved in BP regulation (i.e., neural central and reflex control of sympathetic activity), leading to important increases in BP levels. The evidence is less clear, however, on whether and to what extent advancing age may influence the BP response to acute or chronic high altitude exposure. This is a question not only of scientific interest but also of practical relevance given the consistent number of elderly individuals who are exposed for short time periods (either for leisure or work) or live permanently at high altitude, in whom arterial hypertension is frequently observed. This article will review the evidence available on the relationship between aging and blood pressure levels at high altitude, the pathophysiological mechanisms behind this complex association, as well as some questions of practical interest regarding antihypertensive treatment in elderly subjects, and the effects of antihypertensive drugs on blood pressure response during high altitude exposure.

A large body of evidence has consistently supported the relationship between blood pressure (BP) levels and the risk of cardiovascular complications. In recent years, several independent studies have also indicated that this risk may not only depend on the magnitude of the blood pressure elevation per se but also on the presence of other associated conditions such as increased blood pressure variability. This concept has been supported by a series of reports, most of which post hoc analyses of clinical trials in hypertension, showing that increasing values of BP variability (BPV) (either in the short term, in the midterm, or in the long term) may predict development, progression, and severity of cardiac, vascular, and renal organ damage, as well as cardiovascular events and mortality. Remarkably, studies conducted in populations at high cardiovascular risk have shown increasing values of BPV in the individual subjects (so-called intra- or within-individual BPV) to be strong predictors of cardiovascular morbidity and mortality, even to a larger extent than average BP values. However, in subjects at low to moderate cardiovascular risk, the contribution of BPV to cardiovascular risk prediction over and beyond average BP values has been shown to be only moderate. The aim of this paper is to critically review the evidence addressing the prognostic relevance of different components of BPV addressing a yet open question, i.e., whether routine assessment of BPV in clinical practice should be regarded as an additional target of antihypertensive treatment to improve cardiovascular protection.

The medical visit, or more in general the situation of being in a clinical environment, often leads the patient to experience an alerting reaction and a transient increase in blood pressure (BP) levels [1–3], known as the “white coat effect” [4]. This represents a major problem associated with BP measurement in clinical practice, as it prevents BP measures obtained in the clinic from accurately reflecting the “true” subject’s blood pressure values. Although the first description of this phenomenon was performed by the end of the nineteenth century [5], it was thanks to the observations made by studies implementing sophisticated systems for continuous BP monitoring in ambulatory conditions that the nature and mechanisms responsible for the pressor response to the medical visit could be better understood [1, 3]. These pioneering studies not only provided direct and precise quantitative assessment of the BP rise associated with the doctor’s visit but also indicated that it is the alerting reaction and not the cuff inflation at the moment of BP measurement that causes this pressor response [1, 6].

The alerting reaction associated with the doctor’s visit or more in general with the situation of being in a medical environment causes important interference with blood pressure (BP) measurement in the clinical setting, possibly leading to misclassification of BP levels [1]. Indeed, more than 30 % of subjects who present an acute elevation of BP levels in the doctor’s office (white-coat effect, WCE) may be diagnosed as having white-coat hypertension (WCH, or isolated office hypertension, i.e., the condition characterized by persistently elevated office BP levels and normal ambulatory and/or home BP levels). In recognition of this, current hypertension guidelines have included the suspicion of WCH among the clinical indications for performing out-of-office BP monitoring [2, 3]. However, since performing ambulatory BP monitoring in all subjects who present with elevation in BP levels in the medical office is not always feasible, several studies have been conducted in the attempt to identify clinical and demographic factors that could help the practicing physician to suspect WCH and thus to reasonably proceed with performance ambulatory BP monitoring. However, no clear evidence has been so far provided regarding the clinical features that should be considered in order to raise this suspicion. The first pioneering studies implementing continuous intra-arterial BP recordings indicated that the magnitude of the WCE during a physician visit is largely variable among different subjects, which makes it hardly predictable in the individual patient [1]. Moreover, this interindividual variability in the magnitude of the WCE was not entirely explained by differences in clinical or demographic patients’characteristics (i.e., age, sex, 24-h BP levels) nor by the degree of spontaneous 24-h BP variability [1]. Inconclusive have also been the results of studies exploring the role of other potential predictors for WCE and WCH, such as the pressor response to physical and mental laboratory stress, psychobehavioral factors, or physical activity.

An accurate measurement of blood pressure (BP) levels has important implications for clinical decision making, as it is the basis for a reliable diagnosis of hypertension and for assessment of BP control in treated subjects. The BP rise associated with the alerting reaction during the medical visit, the so-called white coat effect (WCE), represents a major problem associated with conventional BP measurement as it may lead to overestimation of initial BP levels in the absence of treatment and/or to underestimation of the effect of antihypertensive drugs in treated subjects. As a consequence of this, there will be a significant number of subjects with elevated BP levels in the office but with persistently normal out-of-office BP levels (a condition defined as “white coat” hypertension, WCH, or “isolated office” hypertension). Likewise, a considerable number of treated subjects will have apparent resistant hypertension in the office, despite achieving adequate out-of-office BP control with antihypertensive drugs (a condition defined as white coat resistant hypertension, WCRH). From a practical standpoint, the quantification of the magnitude of the WCE would allow estimating subjects’ actual BP levels, thus reducing misclassification of hypertension and providing a better assessment of BP control. However, an accurate and direct estimation of the WCE requires implementation of complex and sophisticated BP measurement techniques (i.e., beat-to-beat BP recordings) before, during, and after the medical visit [1, 2] which prevents it to be obtained routinely either in a clinical setting or in population studies. To overcome these difficulties, alternative, indirect approaches for estimation of the alarm reaction to the medical visit, based on discontinuous ambulatory BP recordings, have been proposed. The most popular of these indirect methods for the assessment of the WCE consists in the straightforward estimation of the difference between clinic BP and average daytime ambulatory BP levels (measured either with ambulatory or home BP monitoring) [3, 4]. By using this methodology, it is also possible to identify WCH (elevated in-office but normal out-of-office blood pressure levels) as well as WCRH (apparent resistant hypertension based on the finding of persisting elevated OBP measures accompanied by adequate control of out-of-office BP levels) in treated subjects. Since both of these conditions occur with a relatively high frequency in clinical practice, current hypertension guidelines [5, 6] have included suspicion of WCH in untreated patients among the clinical indications for out-of-office BP monitoring. Along the same line, guidelines for the management of resistant hypertension request as a mandatory step the exclusion of WCRH by means of a 24-h ambulatory BP monitoring, before proceeding with any interventional therapy of this condition [7].