Sleep-time ambulatory blood pressure as a prognostic marker of vascular and other risks and therapeutic target for prevention by hypertension chronotherapy: Rationale and design of the Hygia Project

This article describes the rationale, objectives, design and conduct of the ambulatory blood pressure monitoring (ABPM)-based Hygia Project. Given the substantial evidence of the significantly better prognostic value of ABPM compared to clinic BP measurements, several international guidelines now propose ABPM as a requirement to confirm the office diagnosis of hypertension. Nonetheless, all previous ABPM outcome investigations, except the Monitorización Ambulatoria para Predicción de Eventos Cardiovasculares study (MAPEC) study, relied upon only a single, low-reproducible 24 h ABPM assessment per participant done at study inclusion, thus precluding the opportunity to explore the potential reduction in cardiovascular disease (CVD) risk associated with modification of prognostic ABPM-derived parameters by hypertension therapy. The findings of the single-center MAPEC study, based upon periodic systematic 48 h ABPM evaluation of all participants during a median follow-up of 5.6 years, constitute the first proof-of-concept evidence that the progressive reduction of the asleep systolic blood pressure (SBP) mean and correction of the sleep-time relative SBP decline toward the normal dipper BP profile, most efficiently accomplished by a bedtime hypertension treatment strategy, best attenuates the risk of CVD, stroke and development of new-onset diabetes. The Hygia Project, primarily designed to extend the use of ABPM in primary care as a requirement for diagnosis of hypertension, evaluation of response to treatment and individualized assessment of CVD and other risks, is a research network presently composed of 40 clinical sites and 292 investigators. Its main objectives are to (i) investigate whether specific treatment-induced changes in ABPM-derived parameters reduce risk of CVD events, stroke, new-onset diabetes and/or development of chronic kidney disease (CKD); and (ii) test the hypothesis that bedtime chronotherapy entailing the entire daily dose of ≥1 conventional hypertension medications exerts better ambulatory BP control and CVD, metabolic and renal risk reduction than all such medications ingested in the morning upon awakening. Between 2007 and 2015, investigators recruited 18 078 persons [9769 men/8309 women, 59.1 ± 14.3 years of age (mean ± SD)], including 15 764 with hypertension according to ABPM criteria as participants in the prospective randomized chronotherapy trial. The initial evaluation includes 48 h ABPM, detailed medical history and screening laboratory blood and urine tests. The same evaluation procedure is scheduled annually, or more frequently when treatment adjustment is required for proper ambulatory BP control, targeting a median follow-up of >5 years. The primary CVD outcome end point is the composite of CVD death, myocardial infarction, coronary revascularization, heart failure, ischemic stroke and hemorrhagic stroke. The independent Hygia Project Events Committee periodically evaluates blinded clinical reports to ascertain and certify every documented event. Beyond the potential findings resulting from testing the main hypotheses, the Hygia Project has already demonstrated, as proof of concept, that the routine diagnosis of hypertension and individualized assessment of CVD and other risks by ABPM, as currently recommended, is fully viable in the primary care setting, where most people with either hypertension, dyslipidemia, type 2 diabetes or CKD receive routine medical attention.     

Chronotherapy of hypertension: advantages of 48-h ambulatory blood pressure monitoring assessments in MAPEC and Hygia Chronotherapy Trial

ABSTRACT

The specific purpose of this communication is to summarize the relevant details of the methods utilized to conduct, analyze, and interpret the ambulatory blood pressure (BP) monitoring (ABPM)-obtained patient data in both MAPEC and Hygia Chronotherapy Trial, including details of the sampling requirements in terms of duration and frequency, proper calculation of ABPM-derived mean values, prognostic and therapeutic implications of BP dipping, and limitations of the 24 h BP mean as diagnostic/prognostic parameter still mistakenly recommended by some hypertension guidelines.     

Bedtime hypertension chronotherapy best reduces cardiovascular disease risk as documented by MAPEC and Hygia Chronotherapy outcomes trials

ABSTRACT

The purpose of this communication is to describe the unique features of the investigative protocols of both MAPEC and Hygia Chronotherapy Trial and to discuss in detail the advantages, limitations, and potential implications of their findings, both for the diagnosis and management of true arterial hypertension that we propose must be defined according to ambulatory blood pressure monitoring (ABPM)-based criteria. In particular, the recommended approach for diagnosis and follow-up of hypertension derived from the findings of MAPEC and Hygia Chronotherapy Trial entails baseline 48-h ABPM assessment for both proper diagnosis of true arterial hypertension and establishment of the eventual need of therapeutic intervention, plus follow-up by periodic 48-h ABPM assessment, specifically for evaluation of timed treatment efficacy and safety.     

The Hygia Project and Hygia Chronotherapy Trial: insights of we clinical investigators on the impact of the embedded continuing medical education on primary-care practice and improved patient cardiovascular health

ABSTRACT

The participating doctors of the Hygia Chronotherapy Trial (HCT) are aware of the criticisms of its published findings, which have been unjustifiably misrepresented in letters to the editors and commentaries, perhaps because of lack of understanding of the foundations of the Hygia Project, in which the HCT is nested. Thus, our purpose through this communication is to highlight the unique features of the Hygia Project and HCT in terms of: (i) organization, management, and quality control, (ii) physician training/continuing medical education, and (iii) impact on every-day primary-care clinical practice specifically improved patient care through 48 h ambulatory blood pressure monitoring to diagnose and optimally manage by bedtime hypertension chronotherapy true arterial hypertension to markedly improve the cardiovascular health of our patients.     

Effects of Time-of-Day of Hypertension Treatment on Ambulatory Blood Pressure and Clinical Characteristics of Patients With Type 2 Diabetes

Generally, hypertensive patients ingest all their blood pressure (BP)-lowering agents in the morning. However, many published prospective trials have reported clinically meaningful morning-evening, treatment-time differences in BP-lowering efficacy, duration of action, and safety of most classes of hypertension medications, and it was recently documented that routine ingestion of ≥1 hypertension medications at bedtime, compared with ingestion of all of them upon awakening, significantly reduces cardiovascular disease (CVD) events. Non-dipping (<10% decline in asleep relative to awake BP mean), as determined by ambulatory BP monitoring (ABPM), is frequent in diabetes and is associated with increased CVD risk. Here, we investigated the influence of hypertension treatment-time regimen on the circadian BP pattern, degree of BP control, and relevant clinical and analytical parameters of hypertensive patients with type 2 diabetes evaluated by 48-h ABPM. This cross-sectional study involved 2429 such patients (1465 men/964 women), 65.9?±?10.6 (mean?±?SD) yrs of age, enrolled in the Hygia Project, involving primary care centers of northwest Spain and designed to evaluate prospectively CVD risk by ABPM. Among the participants, 1176 were ingesting all BP-lowering medications upon awakening, whereas 1253 patients were ingesting ≥1 medications at bedtime. Among the latter, 336 patients were ingesting all BP-lowering medications at bedtime, whereas 917 were ingesting the full daily dose of some hypertension medications upon awakening and the full dose of others at bedtime. Those ingesting ≥1 medications at bedtime versus those ingesting all medications upon awakening had lower likelihood of metabolic syndrome and chronic kidney disease (CKD); had significantly lower albumin/creatinine ratio, glucose, total cholesterol, and low-density lipoprotein (LDL) cholesterol; and had higher estimated glomerular filtration rate and high-density lipoprotein (HDL) cholesterol. Moreover, patients ingesting all medications at bedtime had lowest fasting glucose, serum creatinine, uric acid, and prevalence of proteinuria and CKD. Ingestion of ≥1 medications at bedtime was also significantly associated with lower asleep systolic (SBP) and diastolic BP (DBP) means than treatment with all medications upon awakening. Sleep-time relative SBP and DBP decline was significantly attenuated in patients ingesting all medications upon awakening (p?<?.001). Thus, the prevalence of non-dipping was significantly higher when all hypertension medications were ingested upon awakening (68.6%) than when ≥1 of them was ingested at bedtime (55.8%; p?<?.001 between groups), and even further attenuated (49.7%) when all of them were ingested at bedtime (p?<?.001). Additionally, prevalence of the riser BP pattern, associated with highest CVD risk, was much greater (23.6%) among patients ingesting all medications upon awakening, compared with those ingesting some (20.0%) or all medications at bedtime (12.2%; p?<?.001 between groups). The latter group also showed significantly higher prevalence of properly controlled ambulatory BP (p <?.001) that was achieved by a significantly lower number of hypertension medications (p?<?.001) compared with patients treated upon awakening. Our findings demonstrate significantly lower asleep SBP mean and attenuated prevalence of a blunted nighttime BP decline, i.e., lower prevalence of markers of CVD risk, and improved metabolic profile in patients with type 2 diabetes ingesting hypertension medications at bedtime than in those ingesting all of them upon awakening. These collective findings indicate that bedtime hypertension treatment, in conjunction with proper patient evaluation by ABPM to corroborate the diagnosis of hypertension and avoid treatment-induced nocturnal hypotension, should be the preferred therapeutic scheme for type 2 diabetes. (Author correspondence: rhermida@uvigo.es)     

Prevalence and Clinical Characteristics of Isolated-Office and True Resistant Hypertension Determined by Ambulatory Blood Pressure Monitoring

Hypertension is defined as resistant to treatment when a therapeutic plan including ≥3 hypertension medications failed to sufficiently lower systolic (SBP) and diastolic (DBP) blood pressures (BPs). Most individuals, including those under hypertension therapy, show a “white-coat” effect that could cause an overestimation of their real BP. The prevalence and clinical characteristics of “white-coat” or isolated-office resistant hypertension (RH) has always been evaluated by comparing clinic BP values with either daytime home BP measurements or the awake BP mean obtained from ambulatory monitoring (ABPM), therefore including patients with either normal or elevated asleep BP mean. Here, we investigated the impact of including asleep BP mean as a requirement for the definition of hypertension on the prevalence, clinical characteristics, and estimated cardiovascular (CVD) risk of isolated-office RH. This cross-sectional study evaluated 3042 patients treated with ≥3 hypertension medications and evaluated by 48-h ABPM (1707 men/1335 women), 64.2?±?11.6 (mean?±?SD) yrs of age, enrolled in the Hygia Project. Among the participants, 522 (17.2%) had true isolated-office RH (elevated clinic BP and controlled awake and asleep ambulatory BPs while treated with 3 hypertension medications), 260 (8.6%) had false isolated-office RH (elevated clinic BP, controlled awake SBP/DBP means, but elevated asleep SBP or DBP mean while treated with 3 hypertension medications), and the remaining 2260 (74.3%) had true RH (elevated awake or asleep SBP/DBP means while treated with 3 medications, or any patient treated with ≥4 medications). Patients with false, relative to those with true, isolated-office RH had higher prevalence of microalbuminuria and chronic kidney disease (CKD), significantly higher albumin/creatinine ratio (p <?.001), significantly higher 48-h SBP/DBP means by 9.6/5.3?mm Hg (p?<?.001), significantly lower sleep-time relative SBP and DBP decline (p?<?.001), and significantly greater prevalence of a non-dipper BP profile (96.9% vs. 38.9%; p?<?.001). Additionally, the prevalence of the riser BP pattern, which is associated with highest CVD risk, was much greater, 40.4% vs. 5.0% (p?<?.001), among patients with false isolated-office RH. The estimated hazard ratio of CVD events, using a fully adjusted model including the significant confounding variables of sex, age, diabetes, chronic kidney disease, asleep SBP mean, and sleep-time relative SBP decline, was significantly greater for patients with false compared with those with true isolated-office RH (2.13 [95% confidence interval: 1.95–2.32]; p?<?.001). Patients with false isolated-office hypertension and true RH, however, were equivalent for the prevalence of obstructive sleep apnea, metabolic syndrome, obesity, diabetes, microalbuminuria, and chronic kidney disease, and they had an equivalent estimated hazard ratio of CVD events (1.04 [95% confidence interval: .97–1.12]; p?=?.265). Our findings document a significantly elevated prevalence of a blunted nighttime BP decline in patients here categorized as either false isolated-office RH and true RH, jointly accounting for 82.8% of the studied sample. Previous reports of much lower prevalence of true RH plus a nonsignificant increased CVD risk of this condition compared with isolated-office RH are misleading by disregarding asleep BP mean for classification. Our results further indicate that classification of RH patients into categories of isolated-office RH, masked RH, and true RH cannot be based on the comparison of clinic BP with either daytime home BP measurements or awake BP mean from ABPM, as so far customary in the available literature, totally disregarding the highly significant prognostic value of nighttime BP. Accordingly, ABPM should be regarded as a clinical requirement for proper diagnosis of true RH. (Author correspondence: rhermida@uvigo.es)     

Comparison of Ambulatory Blood Pressure Parameters of Hypertensive Patients With and Without Chronic Kidney Disease

There is strong association between chronic kidney disease (CKD) and increased prevalence of hypertension, risk of end-organ damage, and cardiovascular disease (CVD). Non-dipping, as determined by ambulatory blood pressure (BP) monitoring (ABPM), is frequent in CKD and has also been consistently associated with increased CVD risk. The reported prevalence of non-dipping in CKD is highly variable, probably due to relatively small sample sizes, reliance only on a single, low-reproducibility, 24-h ABPM evaluation per participant, and definition of daytime and nighttime periods by arbitrary fixed clock-hour spans. Accordingly, we assessed the circadian BP pattern of patients with and without CKD by 48-h ABPM to increase reproducibility of the results. This cross-sectional study involved 10 271 hypertensive patients (5506 men/4765 women), 58.0?±?14.2 (mean?±?SD) yrs of age, enrolled in the Hygia Project. Among the participants, 3227 (1925 men/1302 women) had CKD. At the time of recruitment, 568/2234 patients with/without CKD were untreated for hypertension. Patients with than without CKD were more likely to be men and of older age, have diagnoses of obstructive sleep apnea, metabolic syndrome, diabetes, and/or obesity, plus have higher glucose, creatinine, uric acid, and triglyceride, but lower cholesterol, concentrations. In patients with CKD, ambulatory systolic BP (SBP) was significantly elevated (p?<?.001), mainly during the hours of nighttime sleep, independent of presence/absence of BP-lowering treatment. In patients without CKD, ambulatory diastolic BP (DBP), however, was significantly higher (p?<?.001), mainly during the daytime. Differing trends for SBP and DBP between groups resulted in large differences in ambulatory pulse pressure (PP), it being significantly greater (p?<?.001) for the entire 24?h in patients with CKD. Prevalence of non-dipping was significantly higher in patients with than without CKD (60.6% vs. 43.2%; p?<?.001). The largest difference between groups was in the prevalence of the riser BP pattern, i.e., asleep SBP mean?>?awake SBP mean (17.6% vs. 7.1% in patients with and without CKD, respectively; p?<?.001). The riser BP pattern significantly and progressively increased from 8.1% among those with stage 1 CKD to a very high 34.9% of those with stage 5 CKD. Elevated asleep SBP mean was the major basis for the diagnosis of hypertension and/or inadequate BP control among patients with CKD; thus, among the uncontrolled hypertensive patients with CKD, 90.7% had nocturnal hypertension. Our findings document significantly elevated prevalence of a blunted nocturnal BP decline in hypertensive patients with CKD. Most important, prevalence of the riser BP pattern, associated with highest CVD risk among all possible BP patterns, was 2.5-fold more prevalent in CKD, and up to 5-fold more prevalent in end-stage renal disease. Patients with CKD also presented significantly elevated ambulatory PP, reflecting increased arterial stiffness and enhanced CVD risk. Collectively, these findings indicate that CKD should be included among the clinical conditions for which ABPM is mandatory for proper diagnosis and CVD risk assessment, as well as a means to establish the best therapeutic scheme to increase CVD event-free survival. (Author correspondence: rhermida@uvigo.es)     

Circadian Pattern of Ambulatory Blood Pressure in Hypertensive Patients With and Without Type 2 Diabetes

There is strong association between diabetes and increased risk of end-organ damage, stroke, and cardiovascular disease (CVD) morbidity and mortality. Non-dipping (<10% decline in the asleep relative to awake blood pressure [BP] mean), as determined by ambulatory BP monitoring (ABPM), is frequent in diabetes and consistently associated with increased CVD risk. The reported prevalence of non-dipping in diabetes is highly variable, probably due to differences in the study groups (normotensive subjects, untreated hypertensives, treated hypertensives), relatively small sample sizes, reliance only on a single, low-reproducibility, 24-h ABPM evaluation per participant, and definition of daytime and nighttime periods by arbitrary selected fixed clock-hour spans. Accordingly, we evaluated the influence of diabetes on the circadian BP pattern by 48-h ABPM (rather than for 24?h to increase reproducibility of results) during which participants maintained a diary listing times of going to bed at night and awakening in the morning. This cross-sectional study involved 12 765 hypertensive patients (6797 men/5968 women), 58.1?±?14.1 (mean?±?SD) yrs of age, enrolled in the Hygia Project, designed to evaluate prospectively CVD risk by ABPM in primary care centers of northwest Spain. Among the participants, 2954 (1799 men/1155 women) had type 2 diabetes. At the time of study, 525/3314 patients with/without diabetes were untreated for hypertension, and the remaining 2429/6497 patients with/without diabetes were treated. Hypertension was defined as awake systolic (SBP)/diastolic (DBP) BP mean ≥135/85?mm Hg, or asleep SBP/DBP mean ≥120/70?mm Hg, or BP-lowering treatment. Hypertensive patients with than without diabetes were more likely to be men and of older age, have diagnoses of microalbuminuria, proteinuria, chronic kidney disease, obstructive sleep apnea, metabolic syndrome, and/or obesity, plus higher glucose, creatinine, uric acid, and triglycerides, but lower cholesterol and estimated glomerular filtration rate. In patients with diabetes, ambulatory SBP was significantly elevated (p?<?.001), mainly during the hours of nighttime sleep and initial hours after morning awakening, independent of presence/absence of BP-lowering treatment. Ambulatory DBP, however, was significantly higher (p?<?.001) in patients without diabetes, mainly during the daytime. Differing trends for SBP and DBP between groups resulted in large differences in ambulatory pulse pressure (PP), it being significantly greater (p?<?.001) throughout the entire 24?h in patients with diabetes, even after correcting for age. Prevalence of non-dipping was significantly higher in patients with than without diabetes (62.1% vs. 45.9%; p?<?.001). Largest difference between groups was in the prevalence of the riser BP pattern, i.e., asleep SBP mean greater than awake SBP mean (19.9% vs. 8.1% in patients with and without diabetes, respectively; p?<?.001). Elevated asleep SBP mean was the major basis for the diagnosis of hypertension and/or inadequate BP control among patients with diabetes; thus, among the uncontrolled hypertensive patients with diabetes, 89.2% had nocturnal hypertension. Our findings document significantly elevated prevalence of a blunted nocturnal BP decline in hypertensive patients with diabetes. Most important, prevalence of the riser BP pattern, associated with highest CVD risk among all possible BP patterns, was more than twice as prevalent in diabetes. Patients with diabetes also presented significantly elevated ambulatory PP, reflecting increased arterial stiffness and enhanced CVD risk. These collective findings indicate that diabetes should be included among the clinical conditions for which ABPM is recommended for proper CVD risk assessment. (Author correspondence: rhermida@uvigo.es)     

Guidelines for the design and conduct of human clinical trials on ingestion-time differences – chronopharmacology and chronotherapy – of hypertension medications

ABSTRACT

Current hypertension guidelines fail to provide a recommendation on when-to-treat, thus disregarding relevant circadian rhythms that regulate blood pressure (BP) level and 24 h patterning and medication pharmacokinetics and pharmacodynamics. The ideal purpose of ingestion-time (chronopharmacology, i.e. biological rhythm-dependent effects on the kinetics and dynamics of medications, and chronotherapy, i.e. the timing of pharmaceutical and other treatments to optimize efficacy and safety) trials should be to explore the potential impact of endogenous circadian rhythms on the effects of medications. Such investigations and outcome trials mandate adherence to the basic standards of human chronobiology research. In-depth review of the more than 150 human hypertension pharmacology and therapeutic trials published since 1974 that address the differential impact of upon-waking/morning versus at-bedtime/evening schedule of treatment reveals diverse protocols of sometimes suboptimal or defective design and conduct. Many have been “time-of-day,” i.e. morning versus evening, rather than circadian-time-based, and some relied on wake-time office BP rather than around-the-clock ambulatory BP measurements (ABPM). Additionally, most past studies have been of too small sample size and thus statistically underpowered. As of yet, there has been no consensual agreement on the proper design, methods and conduct of such trials. This Position Statement recommends ingestion-time hypertension trials to follow minimum guidelines: (i) Recruitment of participants should be restricted to hypertensive individuals diagnosed according to ABPM diagnostic thresholds and of a comparable activity/sleep routine. (ii) Tested treatment-times should be selected according to internal biological time, expressed by the awakening and bed times of the sleep/wake cycle. (iii) ABPM should be the primary or sole method of BP assessment. (iv) The minimum-required features for analysis of the ABPM-determined 24 h BP pattern ought to be the asleep (not “nighttime”) BP mean and sleep-time relative BP decline, calculated in reference to the activity/rest cycle per individual. (v) ABPM-obtained BP means should be derived by the so-called adjusted calculation procedure, not by inaccurate arithmetic averages. (vi) ABPM should be performed with validated and calibrated devices at least hourly throughout two or more consecutive 24 h periods (48 h in total) to achieve the highest reproducibility of mean wake-time, sleep-time and 48 h BP values plus the reliable classification of dipping status. (vii) Calculation of minimum required sample size in adherence with proper statistical methods must be provided. (viii) Hypertension chronopharmacology and chronotherapy trials should preferably be randomized double-blind, randomized open-label with blinded-endpoint, or crossover in design, the latter with sufficient washout period between tested treatment-time regimens.     

Blood pressure medication should be routinely dosed at bedtime. An internist’s critical appraisal of the editorial by Rainhold Kreutz et al. (2020). Blood pressure medication should not be routinely dosed at bedtime. We must disregard the data from the HYGIA project. Blood Pressure. 29 (3):135–136

ABSTRACT

The history of hypertension the past hundred years is a successful story of the fall of myths, beliefs, and assumptions under the weight of evidence. The recent editorial by Kreutz et al. (2020),”Blood pressure medication should not be routinely dosed at bedtime. We must disregard the data from the HYGIA project”, published in Blood Pressure, conveys unjustified concerns founded on baseless doubts and suspicions about the Hygia Chronotherapy Trial. The physicians of Portugal are beginning to incorporate into routine clinical practice the proven methods of the Hygia Chronotherapy Trial – 48-hour ambulatory blood pressure monitoring and bedtime hypertension chronotherapy – to improve in a cost-effective matter the diagnosis and management of hypertension and to reduce the overwhelming burden of cardiovascular morbidity and mortality in our country.     

Modeling the circadian variability of ambulatorily monitored blood pressure by multiple-component analysis

The use of a set of new end points derived from ambulatory blood pressure monitoring (ABPM), in addition to the blood pressure (BP) values themselves, has been advocated to improve the sensitivity and specificity in diagnosing hypertension and to evaluate a person's response to treatment. An adequate estimation of rhythmic parameters depends, however, on the ability to describe properly the circadian pattern of BP variability. The purpose of this study was to identify a simple model that could characterize sufficiently well the circadian pattern of BP in normotensive healthy volunteers sampled by ambulatory monitoring. We studied 278 clinically healthy Spanish adults (184 men), 22.7±3.3 yr of age, without medical history of hypertension and mean BP from ambulatory profiles always below 135/85 mmHg for systolic/diastolic BP, who underwent sequential ABPM providing a total of 1115 series of BPs and heart rates (HRs), sampled on each occasion at 0.5h intervals for 48 h. Subjects were assessed while adhering to their usual diurnal activity and nocturnal sleep routine, without restrictions but avoiding the use of medication. The circadian rhythm in BP and HR for each subject was established by multiple-component analysis. A statistically significant 24h component is documented for 97% of the BP profiles, with a significant second (12h) harmonic documented in 65% of the profiles. Other ultradian harmonic components were significant in less than 20% of the profiles. A statistically significant increase in the coefficient of determination (percent of overall variability explained by the function fitted to the data) was only obtained after including the periods of 24 and 12 h for BP, and periods of 24, 12, and 6 h for HR in the model components. Although other ultradian components can be demonstrated as statistically significant in a small percent of subjects, a rather simple model including only the two first harmonics of the 24h period describes sufficiently well, at the specified sampling rate, the circadian pattern of BP in normotensive subjects. Departure from this model could characterize overt pathology, as recently demonstrated in the diagnosis of preeclampsia.     

Modeling the circadian variability of ambulatorily monitored blood pressure by multiple-component analysis

The use of a set of new end points derived from ambulatory blood pressure monitoring (ABPM), in addition to the blood pressure (BP) values themselves, has been advocated to improve the sensitivity and specificity in diagnosing hypertension and to evaluate a person's response to treatment. An adequate estimation of rhythmic parameters depends, however, on the ability to describe properly the circadian pattern of BP variability. The purpose of this study was to identify a simple model that could characterize sufficiently well the circadian pattern of BP in normotensive healthy volunteers sampled by ambulatory monitoring. We studied 278 clinically healthy Spanish adults (184 men), 22.7±3.3 yr of age, without medical history of hypertension and mean BP from ambulatory profiles always below 135/85 mmHg for systolic/diastolic BP, who underwent sequential ABPM providing a total of 1115 series of BPs and heart rates (HRs), sampled on each occasion at 0.5h intervals for 48 h. Subjects were assessed while adhering to their usual diurnal activity and nocturnal sleep routine, without restrictions but avoiding the use of medication. The circadian rhythm in BP and HR for each subject was established by multiple-component analysis. A statistically significant 24h component is documented for 97% of the BP profiles, with a significant second (12h) harmonic documented in 65% of the profiles. Other ultradian harmonic components were significant in less than 20% of the profiles. A statistically significant increase in the coefficient of determination (percent of overall variability explained by the function fitted to the data) was only obtained after including the periods of 24 and 12 h for BP, and periods of 24, 12, and 6 h for HR in the model components. Although other ultradian components can be demonstrated as statistically significant in a small percent of subjects, a rather simple model including only the two first harmonics of the 24h period describes sufficiently well, at the specified sampling rate, the circadian pattern of BP in normotensive subjects. Departure from this model could characterize overt pathology, as recently demonstrated in the diagnosis of preeclampsia.     

Sleep-Time Blood Pressure: Prognostic Value and Relevance as a Therapeutic Target for Cardiovascular Risk Reduction

Correlation between blood pressure (BP) level and target organ damage, cardiovascular disease (CVD) risk, and long-term prognosis is greater for ambulatory BP monitoring (ABPM) than clinical BP measurements. Nevertheless, the latter continue to be the “gold standard” to diagnose hypertension, assess CVD risk, and evaluate hypertension treatment. Independent ABPM studies have found that elevated sleep-time BP is a better predictor of CVD risk than either the awake or 24-h BP mean. A major limitation of all previous ABPM-based prognostic studies is the reliance only upon a single baseline profile from each participant at the time of inclusion, without accounting for potential changes in the level and pattern of ambulatory BP thereafter during follow-up. Accordingly, impact of the alteration over time, i.e., during long-term follow-up, of specific features of the 24-h BP variation on CVD risk has never been properly investigated. We evaluated the comparative prognostic value of (i) clinic and ambulatory BP; (ii) different ABPM-derived characteristics, e.g., asleep or awake BP mean; and (iii) specific changes in ABPM characteristic during follow-up, mainly whether reduced CVD risk is more related to the progressive decrease of asleep or awake BP. We prospectively studied 3344 subjects (1718 men/1626 women), 52.6?±?14.5 (mean?±?SD) yrs of age, during a median follow-up of 5.6 yrs. Those with hypertension at baseline were randomized to ingest all their prescribed hypertension medications upon awakening or ≥1 of them at bedtime. At baseline, BP was measured at 20-min intervals from 07:00 to 23:00?h and at 30-min intervals at night for 48-h, and physical activity was simultaneously monitored every min by wrist actigraphy to accurately derive awake and asleep BP means. Identical assessment was scheduled annually and more frequently (quarterly) if treatment adjustment was required. Data collected either at baseline or the last ABPM evaluation per participant showed that the asleep systolic BP mean was the most significant predictor of both total CVD events and major CVD events (a composite of CVD death, myocardial infarction, and stroke). Moreover, when the asleep BP mean was adjusted by the awake mean, only the former was a significant independent predictor of outcome in a Cox proportional-hazard model adjusted for sex, age, diabetes, anemia, and chronic kidney disease. Analyses of changes in ambulatory BP during follow-up revealed 17% reduction in CVD risk for each 5?mm Hg decrease in the asleep systolic BP mean (p?<?.001), independent of changes in any other clinic or ambulatory BP parameter. The increased event-free survival associated with the progressive reduction in the asleep systolic BP mean during follow-up was significant for subjects with either normal or elevated BP at baseline. The ABPM-derived asleep BP mean was the most significant prognostic marker of CVD morbidity and mortality. Most important, the progressive decrease in asleep BP mean, a novel therapeutic target that requires proper patient evaluation by ABPM and best achieved by ingestion of at least one hypertension medication at bedtime, was the most significant predictor of event-free survival. (Author correspondence: rhermida@uvigo.es)     

Ambulatory Blood Pressure Monitoring in the Prediction of Cardiovascular Events and Effects of Chronotherapy: Rationale and Design of the MAPEC Study

Ambulatory blood pressure (BP) measurements (ABPM) correlate more closely with target organ damage and cardiovascular events than clinical cuff measurements. ABPM reveals the significant circadian variation in BP, which in most individuals presents a morning increase, small post‐prandial decline, and more extensive lowering during nocturnal rest. However, under certain pathophysiological conditions, the nocturnal BP decline may be reduced (non‐dipper pattern) or even reversed (riser pattern). This is clinically relevant because the non‐dipper and riser circadian BP patterns constitute a risk factor for left ventricular hypertrophy, microalbuminuria, cerebrovascular disease, congestive heart failure, vascular dementia, and myocardial infarction. Hence, there is growing interest in how to best tailor and individualize the treatment of hypertension according to the specific circadian BP pattern of each patient. All previous trials that have demonstrated an increased cardiovascular risk in non‐dipper as compared to dipper patients have relied on the prognostic significance of a single ABPM baseline profile from each participant without accounting for possible changes in the BP pattern during follow‐up. Moreover, the potential benefit (i.e., reduction in cardiovascular risk) associated with the normalization of the circadian BP variability (conversion from non‐dipper to dipper pattern) from an appropriately envisioned treatment strategy is still a matter of debate. Accordingly, the MAPEC (Monitorización Ambulatoria de la Presión Arterial y Eventos Cardiovasculares, i.e., Ambulatory Blood Pressure Monitoring and Cardiovascular Events) study was designed to investigate whether the normalization of the circadian BP profile toward more of a dipper pattern by chronotherapeutic strategies (i.e., specific timing during the 24 h of BP‐lowering medications according to the 24 h BP pattern) reduces cardiovascular risk. The prospective MAPEC study investigates 3,000 diurnally active men and women ≥18 yrs of age. At inclusion, BP and wrist activity are measured for 48 h. The initial evaluation also includes a detailed medical history, an electrocardiogram, and screening laboratory blood and urine tests. The same evaluation procedure is scheduled yearly or more frequently (quarterly) if treatment adjustment is required for BP control. Cardiovascular morbidity and mortality are thus evaluated on the basis of changes in BP during follow‐up. The MAPEC study, now on its fourth year of follow‐up, investigates the potential decrease in cardiovascular, cerebrovascular, and renal risk from the proper modeling of the circadian BP profile by the timed administration (chronotherapy) of antihypertensive medication, beyond the reduction of clinic‐determined daytime or ABPM‐determined 24 h mean BP levels.     

Ambulatory Blood Pressure Monitoring: Importance of Sampling Rate and Duration—48 Versus 24 Hours—on the Accurate Assessment of Cardiovascular Risk

Independent prospective studies have found that ambulatory blood pressure (BP) monitoring (ABPM) is more closely correlated with target organ damage and cardiovascular disease (CVD) risk than clinic BP measurement. This is based on studies in which BP was sampled every 15–30?min for ≤24?h, without taking into account that reproducibility of any estimated parameter from a time series to be potentially used for CVD risk assessment might depend more on monitoring duration than on sampling rate. Herein, we evaluated the influence of duration (48 vs. 24?h) and sampling rate of BP measurements (form every 20–30?min up to every 2?h) on the prognostic value of ABPM-derived parameters. We prospectively studied 3344 subjects (1718 men/1626 women), 52.6?±?14.5 yrs of age, during a median follow-up of 5.6 yrs. Those with hypertension at baseline were randomized to ingest all their prescribed hypertension medications upon awakening or ≥1 of them at bedtime. At baseline, BP was measured at 20-min intervals from 07:00 to 23:00?h and at 30-min intervals at night for 48?h, and physical activity was simultaneously monitored every min by wrist actigraphy to accurately derive the awake and asleep BP means. Identical assessment was scheduled annually and more frequently (quarterly) if treatment adjustment was required. ABPM profiles were modified to generate time series of identical 48-h duration but with data sampled at 1- or 2-h intervals, or shorter, i.e., first 24?h, time series with data sampled at the original rate (daytime 20-min intervals/nighttime 30-min intervals). Bland-Altman plots indicated that the range of individual differences in the estimated awake and asleep systolic (SBP) and diastolic BP (DBP) means between the original and modified ABPM profiles was up to 3-fold smaller for data sampled every 1?h for 48?h than for data sampled every 20–30?min for the first 24?h. Reduction of ABPM duration to just 24?h resulted in error of the estimated asleep SBP mean, the most significant prognostic marker of CVD events, in the range of ?21.4 to +23.9?mm Hg. Cox proportional-hazard analyses adjusted for sex, age, diabetes, anemia, and chronic kidney disease revealed comparable hazard ratios (HRs) for mean BP values and sleep-time relative BP decline derived from the original complete 48-h ABPM profiles and those modified to simulate a sampling rate of one BP measurement every 1 or 2?h. The HRs, however, were markedly overestimated for SBP and underestimated for DBP when the duration of ABPM was reduced from 48 to only 24?h. This study on subjects evaluated prospectively by 48-h ABPM documents that reproducibility in the estimates of prognostic ABPM-derived parameters depends markedly on duration of monitoring, and only to a lesser extent on sampling rate. The HR of CVD events associated with increased ambulatory BP is poorly estimated by relying on 24-h ABPM, indicating ABPM for only 24?h may be insufficient for proper diagnosis of hypertension, identification of dipping status, evaluation of treatment efficacy, and, most important, CVD risk stratification. (Author correspondence: rhermida@uvigo.es)     

Role of Time-of-Day of Hypertension Treatment on the J-Shaped Relationship Between Blood Pressure and Cardiovascular Risk

Several previous studies found that too great a reduction of clinic blood pressure (BP) by treatment increased cardiovascular disease (CVD) risk, whereas moderate reduction decreased it. Thus, it has been suggested that the relationship between BP and CVD events is J-shaped, with CVD risk decreasing as BP is lowered, and then rising as BP is further decreased. Correlation between BP level and CVD risk, however, is stronger for ambulatory BP monitoring (ABPM) than clinical BP measurements. We previously established that the hypertension treatment-time regimen, upon awakening versus at bedtime, exerts differential effect on BP control during the day and nighttime, which translates into a differential degree of CVD risk prevention. We, therefore, investigated the role of hypertension treatment-time scheme on the nature of the relationship between achieved clinic and ambulatory BP and CVD risk in the MAPEC (Monitorización Ambulatoria para Predicción de Eventos Cardiovasculares, i.e., Ambulatory Blood Pressure Monitoring for Prediction of Cardiovascular Events) study, a prospective, open-label, blinded-endpoint trial on 2156 hypertensive patients (1044 men/1112 women), 55.6?±?13.6 (mean?±?SD) yrs of age, randomized to ingest all prescribed once-a-day hypertension medications upon awakening or the entire daily dose of ≥1 of them at bedtime. Ambulatory BP was measured for 48-h at baseline and annually thereafter, and more frequently (quarterly) when adjustment of treatment was necessary. After a median follow-up of 5.6 yrs, a J-shaped relationship was detected between total CVD events and clinic as well as awake BP mean, but only for the group of patients ingesting all medications upon awakening. The relationship was different in the group of patients who ingested ≥1 medications at bedtime; the risk of CVD events progressively diminished in a linear, rather than J-shaped, manner with treatment-induced decrease in awake BP mean. The adjusted hazard ratio of CVD events was significantly lower with the progressive reduction in the asleep BP mean, independent of the hypertension treatment-time regimen. There was no single major event, i.e., CVD death, myocardial infarction, or stroke, in patients who achieved an asleep systolic BP mean <103?mm Hg. Our findings indicate that bedtime hypertension treatment is not associated with a J-shaped relationship between achieved BP and CVD risk. The decreased CVD risk associated with the progressive reduction in asleep BP, more feasible by bedtime than morning hypertension treatment, has clinical implications, in particular, the need to consider the proper timing of hypertension medications, in conjunction with ABPM for proper assessment of BP control, as an improved and potentially safer means of reducing CVD risk of hypertensive patients. (Author correspondence: rhermida@uvigo.es)     

Time-Qualified Reference Limits (Chronodesms) for 24-Hour Blood Pressure Values: Classical and Bayesian

Background – This paper is a concrete example of the problems raised by the need of constructing the time-qualified reference limits (chronodesms) for blood pressure (BP), in order to clinically estimate the hemodynamic parameter in its intrinsic nychtohemeral variability. Methods – Assuming that the noninvasive ambulatory BP monitoring (ABPM) is the eligible technique for this need, it must be realized that the BP chronodems may be of two types, depending on the sample being used for their calculation. The first type may be regarded as “ a priori ” because of the fact that they are derived by a sample of normotensive subjects who are unavoidably recruited via “ causal ” sphygmomanometric measurements and reclassified as normotensive by comparing their ABPM to the fixed reference limits (monodesms) given by WHO (monodiagnosis). Therefore, the “ a priori ” BP chonodesms are by principle derived by subjects who could not be correctly classified as normotensive, their ABPM being not tested versus the time-varying physiological limits. The second type may regarded as “ a posteriori ” in virtue of the fact that they may be constructed on a sample which contemplates the previous subjects who result to be true normotensive via the reassessment of their ABPM versus the “ a priori ” BP chronodesms (chronodiagnosis). The “ a posteriori ” chronodesms may be regarded as biometrically reliable, whether the sample for their construction is additionally constituted by those subjects of the local population who have been erroneously monodiagnosed as hypertensive, while they result to be true normotensive via the chronodiagnostic comparison of their ABPM versus the “ a priori ” BP chronodesms. Results – The biometric reliability of the “ a posteriori ” BP chronodems is demonstrated by the fact that their upper limits are statistically significantly less pronounced due to the fact that they are provided by a sample which has been depured by the falsely monodiagnosed normotensives. Conclusions – The “ a posteriori ” BP upper chronodesms are the time-qualified reference limits which should be used in clinical practice for the chronodiagnosis of hypertension.     

Ambulatory Blood Pressure Monitoring for the Early Identification of Hypertension in Pregnancy

Gestational hypertension and preeclampsia are major contributors to perinatal morbidity and mortality. The diagnosis of gestational hypertension still relies on conventional clinic blood pressure (BP) measurements and thresholds of ≥140/90?mm Hg for systolic (SBP)/diastolic (DBP) BP. However, the correlation between BP level and target organ damage, cardiovascular disease risk, and long-term prognosis is greater for ambulatory BP monitoring (ABPM) than clinic BP measurement. Accordingly, ABPM has been suggested as the logical approach to overcoming the low sensitivity and specificity of clinic BP measurements in pregnancy. With the use of ABPM, differing predictable BP patterns throughout gestation have been identified for clinically healthy and hypertensive pregnant women. In normotensive pregnancies, BP steadily decreases up to the middle of gestation and then increases up to the day of delivery. In contrast, women who develop gestational hypertension or preeclampsia show stable BP during the first half of pregnancy and a continuous linear BP increase thereafter until delivery. Epidemiologic studies have also consistently reported sex differences in the 24-h patterns of ambulatory BP and heart rate. Typically, men exhibit a lower heart rate and higher BP than women, the differences being larger for SBP than DBP. Additionally, as early as in the first trimester of gestation, statistically significant increased 24-h SBP and DBP means characterize women complicated with gestational hypertension or preeclampsia compared with women with uncomplicated pregnancies. However, the normally lower BP in nongravid women as compared with men, additional decrease in BP during the second trimester of gestation in normotensive but not in hypertensive pregnant women, and significant differences in the 24-h BP pattern between healthy and complicated pregnancies at all gestational ages have not been taken into consideration when establishing reference BP thresholds for the diagnosis of hypertension in pregnancy. Several studies reported that use of the 24-h BP mean is not a proper test for an individualized early diagnosis of hypertension in pregnancy defined on the basis of cuff BP measurements, thus concluding that from such an awkward approach ABPM is not useful in pregnancy. The 24-h BP pattern that characterizes healthy pregnant women at all gestational ages suggests the use for diagnosis of a time-specified reference limit reflecting that mostly predictable BP variability. Once the time-varying threshold, given, for instance, by the upper limit of a tolerance interval, is available, the hyperbaric index (HBI), as a determinant of BP excess, can be calculated as the total area of any given subject's BP above the threshold. This tolerance-hyperbaric test, where diagnosis of gestational hypertension is based on the HBI calculated with reference to a time-specified tolerance limit, has been shown to provide high sensitivity and specificity for the early identification of subsequent hypertension in pregnancy, as well as a valuable approach for prediction of pregnancy outcome. ABPM during gestation, starting preferably at the time of the first obstetric check-up following positive confirmation of pregnancy, provides sensitive endpoints for use in early risk assessment and guide for establishing prophylactic or therapeutic intervention, and should thus be regarded as the required standard for the diagnosis of hypertension in pregnancy. (Author correspondence: rhermida@uvigo.es)     

Ambulatory blood pressure monitoring in the prediction of cardiovascular events and effects of chronotherapy: rationale and design of the MAPEC study

Ambulatory blood pressure (BP) measurements (ABPM) correlate more closely with target organ damage and cardiovascular events than clinical cuff measurements. ABPM reveals the significant circadian variation in BP, which in most individuals presents a morning increase, small post-prandial decline, and more extensive lowering during nocturnal rest. However, under certain pathophysiological conditions, the nocturnal BP decline may be reduced (non-dipper pattern) or even reversed (riser pattern). This is clinically relevant because the non-dipper and riser circadian BP patterns constitute a risk factor for left ventricular hypertrophy, microalbuminuria, cerebrovascular disease, congestive heart failure, vascular dementia, and myocardial infarction. Hence, there is growing interest in how to best tailor and individualize the treatment of hypertension according to the specific circadian BP pattern of each patient. All previous trials that have demonstrated an increased cardiovascular risk in non-dipper as compared to dipper patients have relied on the prognostic significance of a single ABPM baseline profile from each participant without accounting for possible changes in the BP pattern during follow-up. Moreover, the potential benefit (i.e., reduction in cardiovascular risk) associated with the normalization of the circadian BP variability (conversion from non-dipper to dipper pattern) from an appropriately envisioned treatment strategy is still a matter of debate. Accordingly, the MAPEC (Monitorización Ambulatoria de la Presión Arterial y Eventos Cardiovasculares, i.e., Ambulatory Blood Pressure Monitoring and Cardiovascular Events) study was designed to investigate whether the normalization of the circadian BP profile toward more of a dipper pattern by chronotherapeutic strategies (i.e., specific timing during the 24 h of BP-lowering medications according to the 24 h BP pattern) reduces cardiovascular risk. The prospective MAPEC study investigates 3,000 diurnally active men and women >/=18 yrs of age. At inclusion, BP and wrist activity are measured for 48 h. The initial evaluation also includes a detailed medical history, an electrocardiogram, and screening laboratory blood and urine tests. The same evaluation procedure is scheduled yearly or more frequently (quarterly) if treatment adjustment is required for BP control. Cardiovascular morbidity and mortality are thus evaluated on the basis of changes in BP during follow-up. The MAPEC study, now on its fourth year of follow-up, investigates the potential decrease in cardiovascular, cerebrovascular, and renal risk from the proper modeling of the circadian BP profile by the timed administration (chronotherapy) of antihypertensive medication, beyond the reduction of clinic-determined daytime or ABPM-determined 24 h mean BP levels.