Deep immunophenotyping reveals associations with human blood pressure

Introduction For practical reasons, blood pressure values measured by physicians or nurses in a medical environment remain the clinical basis of the diagnosis and management of arterial hypertension around the world as recommended by all guidelines [1–4]. Nevertheless, measurements of blood pressure outside the office have gained an increasing popularity over the last decades not only to ascertain the diagnosis of hypertension but also to follow the impact of therapeutic interventions. Out-of-office blood pressure measurements can be obtained either by 24-h ambulatory blood pressure monitoring or by home blood pressure monitoring. As reviewed recently [5], both sets of out-of-office blood pressure offer undeniable advantages when compared to office blood pressure. First, both ambulatory blood pressure and home blood pressure monitoring provide more reliable and reproducible information on blood pressure. Second, blood pressure values obtained by ambulatory blood pressure and home blood pressure monitoring appear to be more closely related to target organ damage than office blood pressure and hence have a greater prognostic relevance than office blood pressure. Third, certain diagnosis such as white coat hypertension and masked hypertension can only be diagnosed using out-of-office blood pressure measurements. Fourth, when used in the clinical follow-up of treated hypertensive patients to evaluate the impact of drug treatment, ambulatory blood pressure monitoring as well as home blood pressure monitoring has the advantage of not being affected by a placebo effect. Finally, evidence has been provided that treatment-induced reduction in 24-h blood pressure may predict better than office blood pressure the regression of end organ damage (particularly the cardiac one) induced by antihypertensive drug. Many of these information have been achieved during the past two decades by a number of studies carried out in different populations around the world, including the Pressioni Arteriose Monitorate E Loro Associazioni (PAMELA) study [6–10]. When should out-office blood pressure be measured? Despite their advantages, ambulatory blood pressure monitoring as well as home blood pressure monitoring is not regarded as a routine procedure that should be applied to all hypertensive patients essentially for economical reasons. However, this issue is debated because the clinical information gathered with these measurements may potentially result in financial savings when applied adequately. The European and American guidelines for the management of hypertension have defined some indications for the use of ambulatory blood pressure monitoring in hypertension [1,2]. These include patients with resistant hypertension, patients with a high variability of office blood pressure, low-risk patients with a high blood pressure, patients with suspected episodes of hypotension, patients with a large discrepancy between office and home blood pressures, and finally patients with special clinical conditions such as pregnancy or sleep apnea syndrome. Outside these indications, the use of ambulatory blood pressure monitoring could be discussed both in terms of feasibility and economics. Theoretically, a measurement of out-of-office blood pressure could be recommended to all new patients with as suspected hypertension to confirm the diagnosis of hypertension and to refine the patient's cardiovascular risk profile. Therefore, ambulatory blood pressure monitoring could be recommended to all high cardiovascular risk patients before starting any treatment and later under therapy to ascertain the adequacy of the control of blood pressure. Ambulatory blood pressure values in diabetic patients In this issue of the Journal of Hypertension, Leitao et al.[11] report the results of a cross-sectional study performed to estimate the daytime ambulatory blood pressure monitoring values corresponding to the target office blood pressure of 130/80 mmHg for diabetic (as defined by the American Diabetes Association) and to assess which diabetic patients may actually benefit from ambulatory blood pressure monitoring. They included 554 patients in this analysis. Regression analyses were performed to analyze the ambulatory blood pressure monitoring values corresponding to office blood pressure and receiver operating characteristics (ROC) curves were used to assess the sensitivity and specificity of office blood pressure in diagnosing daytime ambulatory blood pressure monitoring hypertension. According to their regression equations, the daytime ambulatory blood pressure monitoring corresponding to the target office blood pressure of 130/80 mmHg was 129/79 mmHg and the daytime ambulatory blood pressure monitoring value corresponding to 140/90 mmHg at the office was 134/82 mmHg. As expected, discrepancies between ambulatory blood pressure monitoring and office blood pressure were due essentially to masked hypertension (about 10% of cases) and white coat hypertension (between 19% for systolic blood pressure and 26% for diastolic blood pressure). Interestingly, when office blood pressure was lower than 120 mmHg systolic and 70 mmHg diastolic, the sensitivity to rule out hypertension using ambulatory blood pressure monitoring was 90%. Similarly, when office blood pressure was more than 145 mmHg systolic and more than 90 mmHg diastolic the sensitivity to confirm hypertension using ambulatory blood pressure monitoring was 90%. Within these two sets of limits, 38% of patients would be misclassified if only office blood pressure values would be considered for the diagnosis. Thus, using the cut-off values of less than 120/70 mmHg and more than 140/90 mmHg at the office, 56% of the population sample would need an ambulatory blood pressure monitoring to confirm the diagnosis of hypertension. According to these results, only diabetics with an office blood pressure between 120 and 140 mmHg systolic and/or a diastolic blood pressure between 70 and 90 mmHg would really benefit from an out-office assessment of blood pressure. This would limit the use of ambulatory blood pressure monitoring to only 50% of the diabetic patients. Studies implications and limitations The results of this provide interesting practical information on the use of ambulatory blood pressure monitoring in diabetic patients. However, they also have some limitations. The first one is the fact that the entire analysis is based on daytime ambulatory blood pressure only. Although the authors have measured 24-h blood pressure, they have not considered the nighttime blood pressure. This is unfortunate because there is increasing evidence that nighttime is a better predictor of cardiovascular risk than daytime blood pressure. Moreover, diabetic patients are often characterized by an absence of the physiological fall in blood pressure reflecting a nondipping pattern at night. Diabetes may even be the cause of a reverse dipping, that is an increase in blood pressure at night. Both the nondipping and the reverse dipping pattern of blood pressure have been associated with an increased risk of developing target organ damages such as left ventricular hypertrophy, microalbuminuria, renal dysfunction, and cerebral vascular lesions [5,12]. Thus, when assessing the cardiovascular risk profile linked to hypertension in diabetic patients, nighttime blood pressure should be included. Indeed, it is not uncommon in diabetes that daytime normotensive patients exhibit a nocturnal hypertension. This type of patients would be misdiagnosed using the algorithm proposed by the authors. Recently, the results of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial have shown that in diabetic patients the reduction of cardiovascular morbidity and mortality obtained by lowering office blood pressure below 120 mmHg systolic is not greater than that seen reducing blood pressure below 130 mmHg [13]. On the contrary, a systolic blood pressure below 120 mmHg may result in an increased risk of developing cardiac complications, as suggested by the recent post hoc analysis of diabetic patients with coronary heart diseases having participated in the INternational VErapamil SR-Trandolapril (INVEST) Study [14]. If a low blood pressure increases the risk of cardiac complications in diabetics, one might have to reconsider the necessity to perform an ambulatory blood pressure monitoring in diabetic patients with a blood pressure <120/70 mmHg in contrast to the proposals of Leitao et al. Indeed, in treated diabetic patients with a low office blood pressure, ambulatory blood pressure monitoring could be of importance to diagnosis episodes of asymptomatic hypotension episodes which might increase their cardiac risk. Thus, in the analysis of daytime and nighttime blood pressure values, it would be of interest to assess whether the percentage of ambulatory blood pressure values below a certain level is indeed associated with an increased risk of some cardiovascular complications. In this respect, it is important to mention that the analysis presented by Leitao et al. does not provide any information on the presence in this particular patients population of cardiac organ damage. The study also does not provide any data such on the occurrence of cardiovascular events and deaths, as it was not a prospective cohort study. Both these two sets of information should be thus provided by future clinical trials.

How common is isolated nocturnal hypertension?

The Impact of APOL1 on Chronic Kidney Disease and Hypertension.

Ambulatory blood pressure (ABP) monitoring is increasingly recognized as a valuable tool to refine prediction of cardiovascular risk related to blood pressure (BP).1 After the first landmark study published by Perloff and colleagues 24 years ago,2 several longitudinal event-based studies provided unequivocal evidence of an independent association between ABP and risk of cardiovascular disease. Although experimental procedures and statistical analyses varied from study to study, ABP generally improved cardiovascular risk stratification over and beyond traditional risk factors, including clinic BP.3 The Table, obtained through an electronic search of literature using the terms “ambulatory blood pressure” and “prognosis,” shows a list of longitudinal event-based studies performed by independent groups. It is worth noting that the list of available studies is longer because each group generally published other analyses of their database. Only the first-appearing or main contribution from each group has been included in the Table. View this table: Longitudinal Event-Based Studies From Independent Groups That Addressed the Prognostic Value of ABP Article p 2145 Three aspects of available investigations deserve special mention. First, the prognostic value of ABP has been examined not only in subjects with clinical diagnosis of hypertension but also in the general population and in a variety of settings, including diabetes mellitus, renal failure, and cerebrovascular disease. Second, subjects could be untreated or treated at the time of ABP monitoring. This point may raise concerns, because drug treatment could exert unpredictable effects on 24-hour ABP profile and, consequently, interpretation and applicability of results. Third, although a continuous relation emerged in most studies between ABP and cardiovascular risk, several investigators tried to define clinical categories based on arbitrary thresholds of ABP. Although such categories are potentially useful to make diagnostic and therapeutic decisions in clinical practice, their prognostic role requires confirmation from large and independent cohort …

Today, it is universally acknowledged that, in hypertension, the kidney is both culprit and victim.1 Kidney malfunction causes hypertension, and hypertension, in turn, aggravates chronic kidney disease (CKD) and accelerates its progression. High blood pressure (frank hypertension and blood pressure values in the high normal range) are clearly correlated to progressive kidney injury, both in experimental2 and in clinical3 observations. All of the current guidelines4,5 recommend lowering of systolic blood pressure to 130 or 125 mm Hg in CKD, and even lower values are recommended if the target level of proteinuria of <1 g per 24 hours has not been achieved.4 There is good evidence of “renoprotection” by lowering blood pressure in patients with renal disease, at least in the presence of proteinuria.3 In CKD patients without proteinuria, eg, autosomal polycystic kidney disease, further renoprotection cannot be achieved by lowering blood pressure below the target blood pressure recommended in patients without CKD6; nevertheless, these patients have a markedly elevated cardiovascular risk, and more stringent lowering of blood pressure is desirable, because, eg, reduction of left ventricular hypertrophy as an index of cardiovascular risk had been documented in such patients.6 The worldwide problem of neglect of hypertension and of insufficient implementation of antihypertensive treatment in CKD patients prompted the International Society of Nephrology and the International Federation of Kidney Foundations to devote this year’s World Kidney Day (http://www.worldkidneyday.org) on March 12th to the issue …

The increasing use of ambulatory blood pressure monitoring (ABPM) devices in the investigation of hypertension has allowed detailed study of the circadian rhythm of blood pressure variability, the assessment of resistant hypertension, and the syndrome of “white coat” hypertension. The relevance of ABPM to target-organ damage and the complications of hypertension, such as heart attacks and strokes, has only recently gained prominence. There are more than 30 cross-sectional studies that have linked ABPM to hypertensive target-organ damage, including left ventricular hypertrophy (LVH),1 2 microalbuminuria,3 hypertensive retinal changes, and cerebrovascular disease.4 The majority of these studies have consistently reported that patients with an absent or reduced fall in blood pressure at night (referred to as “nondippers”) have more severe target-organ damage, including LVH5 and cerebrovascular disease,4 6 when compared with patients who demonstrate a normal nocturnal fall in blood pressure. For example, Verdecchia et al,7 in a prospective cohort of over 1100 hypertensive patients, reported higher mortality rates both in nondippers and “reverse dippers” and higher cardiovascular morbidity rates in female nondippers compared with dippers.8 In addition, Yamamoto et al9 recently reported that progressive cerebrovascular disease, including silent ischemic lesions and symptomatic stroke, was associated with a reduced nocturnal blood pressure fall in patients with a history of lacunar infarction. In a cross-sectional study of patients admitted with acute stroke (ictus <12 hours), Lip at al10 reported that such patients could generally be classed as nondippers, with higher blood pressures recorded using ABPM (but not using casual manual measurements) in black/Afro-Caribbean patients and also in patients with hemorrhagic stroke. These studies therefore suggest the potential usefulness of ABPM in epidemiological, cohort, or cross-sectional studies and the assessment of ethnic differences, stroke subtypes, and prognosis. A nondipper status …

sponsorship: The European Union (HEALTH-F7-2011-278249 EU-MASCARA, HEALTH-F7-305507 HOMAGE and the European Research Council Advanced Researcher Grant 294713 EPLORE) and the Fonds voor Wetenschappelijk Onderzoek Vlaanderen, Ministry of the Flemish Community, Brussels, Belgium (G.0881.13 and G.0880.13) currently support the Studies Coordinating Centre (Leuven, Belgium). (European Union|HEALTH-F7-2011-278249 EU-MASCARA, European Union|HEALTH-F7-305507 HOMAGE, European Union (European Research Council)|294713 EPLORE, Fonds voor Wetenschappelijk Onderzoek Vlaanderen, Ministry of the Flemish Community, Brussels, Belgium|G.0881.13, Fonds voor Wetenschappelijk Onderzoek Vlaanderen, Ministry of the Flemish Community, Brussels, Belgium|G.0880.13)

We compared the sensitivity of office blood pressure and ambulatory blood pressure monitoring recordings in evaluating the effectiveness of antihypertensive treatment and identified factors related to inadequate blood pressure control among hypertensive stroke survivors. Office blood pressure and ambulatory blood pressure monitoring measurements were performed at 120+/-30 days after ictus in 187 first-ever consecutive hypertensive stroke survivors who were receiving blood pressure-lowering medications according to international guidelines. Handicap was assessed by the modified Rankin Scale. Blood pressure was regarded as controlled if office and daytime ambulatory systolic and diastolic blood pressure values were <140/90 and <135/85 mmHg, respectively. Patients were subclassified according to the degree of their nocturnal systolic blood pressure fall [(mean daytime values-mean night-time values)100/mean daytime values] as dippers (>or=10%), nondippers (>or=0% and <10%) and reverse dippers (<0%). Effective blood pressure control was documented in significantly (P<0.001) fewer patients using ambulatory blood pressure monitoring (32.1%) than those using office recordings (43.3%), whereas in 16% of the study population a masked lack of per-treatment blood pressure control (elevated ambulatory blood pressure in the presence of normal office blood pressure levels) was identified. The distribution of dipping patterns differed significantly (P=0.01) between controlled hypertensive individuals (normal office and ambulatory measurements) and patients with isolated ambulatory hypertension (dippers: 31.3 vs. 10.0%; nondippers:56.9 vs. 53.3%; reverse dippers: 11.8 vs. 36.7%). Logistic regression analysis revealed diabetes mellitus and functional independency (modified Rankin Scale score<2) as independent predictors of inadequate blood pressure control. Ambulatory blood pressure monitoring detects a substantial number of treated hypertensive stroke survivors with a masked lack of per-treatment blood pressure control, who present a higher prevalence of abnormal circadian blood pressure patterns (reverse dipping). Diabetes mellitus and poststroke functional independency are the main factors contributing to inadequate blood pressure control.

As hypertension is an important risk factor for renal allograft failure, we aimed to assess blood pressure control in renal transplant patients with deteriorating graft function using different methods of blood pressure measurements. Forty-nine patients with a graft survival of >1 year, and with more than a two-fold increase in urinary albumin excretion, and/or an increase in serum creatinine level >20% during the previous 12 months, were included. Office blood pressure and home BP were measured, and ambulatory blood pressures were obtained in all patients. The mean office blood pressure (133.2+/-16.3/81.7+/-9.6 mmHg) and 24 h ambulatory blood pressure (133.1+/-12.0/79.8+/-8.3 mmHg) were similar. Home blood pressure in the morning (144.2+/-23.3/87.1+/-12.7 mmHg) and evening (143.2+/-20.6/86.4+/-10.3 mmHg) were significantly higher than ambulatory blood pressure (P<0.001 for both). Only 18% of the patients exhibited a reduction of >or=10% in systolic blood pressure during nighttime while 39% had an overt rise. Adequate blood pressure control was found in 53% of the patients using office blood pressure (<140/90 mmHg), contrasting 29% using home blood pressure (<135/85 mmHg), and 16% using mean 24-h ambulatory blood pressure (<125/80 mmHg). These findings were substantiated by the use of receiver-operating characteristic curve analysis. Using the 24-h blood pressure as a standard, home blood pressure was superior to office blood pressure in estimating blood pressure control in renal transplant patients. Nocturnal hypertension, however, was observed frequently, adding important clinical information about blood pressure control in this high-risk population.

Blood pressure (BP) control is considered the most important treatment for preventing chronic kidney disease (CKD) progression and associated cardiovascular complications. However, clinic BP is insufficient to diagnose hypertension (HT) and to monitor overall BP control because it does not correlate well with ambulatory blood pressure monitoring (ABPM). We enrolled 387 hypertensive CKD patients (stages G1–G4, 58.4% male with median age 61 years) from 3 hospitals in Korea. HT of clinic BP and ABPM was classified as ≥ 140/90 and ≥ 130/80 mmHg, respectively. Clinic BP control rate was 60.2%. The median 24-hour systolic blood pressures (SBPs) of CKD G3b and CKD G4 were significantly higher than those of CKD G1–2 and CKD G3a. However, the median 24-hour SBPs were not different between CKD G1–2 and CKD G3a or between CKD G3b and CKD G4. Of all patients, 5.7%, 38.0%. 42.3%, and 14.0% were extreme-dippers, dippers, non-dippers, and reverse-dippers, respectively. Non-/reverse-dippers independently correlated with higher Ca × P product, higher intact parathyroid hormone (iPTH), and lower albumin. Normal BP was 33.3%, and sustained, masked, and white-coat HT were 29.7%, 26.9%, and 10.1%, respectively. White-coat HT independently correlated with age ≥ 61 years and masked HT independently correlated with CKD G3b/G4. In conclusion, ABPM revealed a high prevalence of non-/reverse-dippers and sustained/masked HT in Korean CKD patients. Clinicians should try to obtain a CKD patient's ABPM, especially among those who are older or who have advanced CKD as well as those with abnormal Ca × P product, iPTH, and albumin.

A comparison of home measurement and ambulatory monitoring of blood pressure in the adjustment of antihypertensive treatment

Hypertension is an established risk factor for stroke, ischemic heart disease,1,2 and renal dysfunction.3 The management and prevention of hypertension are important to the prevention of these diseases. Recent evidence has suggested that hypertension also plays a central role in the underlying pathophysiological condition or at prodromal stages before the development of these diseases. Accumulating evidence also indicates that hypertension seems to be linked with common noncardiovascular diseases including dementia, cancer, oral health diseases (OHDs), and osteoporosis. In this brief review, we organize the reported results about the associations between hypertension and these diseases, discussing mainly epidemiological surveys, with the goal of clarifying the relationships between these diseases and hypertension. ### Atrial Fibrillation Atrial fibrillation (AF) is one of the most common types of chronic arrhythmia and is a risk factor for ischemic stroke.4 The Framingham Heart Study revealed that hypertension increases the risk of AF by factors of 1.5 for men and 1.4 for women.5 The Women’s Health Study and a cohort study of Norwegian men showed that high-normal blood pressure (BP) was associated with incident AF.6,7 All of these cohort studies were conducted in Westerners, and these associations were also confirmed in a recent Japanese cohort study.8 In that investigation, compared with normal BP and normal weight, systolic prehypertension with overweight was shown to be associated with an increased risk of incident AF ( P for interaction=0.04). Arterial stiffness, left ventricular hypertrophy, and increased left atrial size are important mediators of the relationship between BP and incident AF.9 Higher systolic BP (SBP) and overweight may mutually exacerbate left ventricular hypertrophy and hypertension, and consequently, they may synergistically increase the risk of AF. ### Chronic Kidney Disease and High BP Chronic kidney disease (CKD) is characterized by a progressive decline in an individual’s glomerular filtration rate over several decades, …

Accurate blood pressure measurement is critical to successful clinical trials. Concerns about observer errors have led to the use of automated oscillometric devices without evidence that their performance is similar to that of trained observers. This study compares blood pressures obtained by trained observers and with an oscillometric device (Omron 705CP) to 24-h ambulatory blood pressure monitoring. We performed a post-hoc analysis of 313 untreated hypertensive patients at the end of the washout phase of a Novartis hypertension trial. Patients had three seated trained observer mercury auscultatory blood pressure measurements followed by 24-h ambulatory blood pressure monitoring. The next day, the ambulatory blood pressure monitoring was removed and three seated readings were obtained with an Omron 705CP. Correlations for systolic blood pressure and diastolic blood pressure were obtained between daytime ambulatory blood pressure monitoring (0900 and 2100) and the two office methods. In addition, we investigated the degree of difference of trained observer and Omron measurements from ambulatory blood pressure monitoring. For systolic blood pressure, the correlation with ambulatory blood pressure monitoring of the trained observer was significantly better than with that of the Omron 705CP (0.641 vs. 0.555, P=0.01). For diastolic blood pressure values, even greater disparity between the two office method correlations with ambulatory blood pressure monitoring was observed (trained observer=0.593 vs. Omron=0.319, P<0.0001). Both trained observer and Omron readings were consistently higher than ambulatory blood pressure monitoring for systolic blood pressure (P<0.0001) and diastolic blood pressure (P<0.0001). Omron measurements, however, deviated from ambulatory blood pressure monitoring more than those of the trained observer (P<0.0001 for systolic blood pressure and diastolic blood pressure). For clinical trials using diastolic blood pressure targets, the Omron 705CP cannot replace the auscultatory blood pressure measurements of a trained observer. For systolic blood pressure, the Omron device and the trained observer had similar correlations with ambulatory blood pressure monitoring; however, both methods gave consistently higher systolic blood pressure values. Further study of oscillometric devices should be conducted before universally replacing auscultatory blood pressure determinations by trained observers in clinical trials.

We agree with Professor Bulpitt (1) that if a study on antihypertensive treatment is not placebo controlled, clinic blood pressure and side-effect data have a limited scientific value. For this reason, we reported them briefly (to characterize our population by a commonly used set of values) and focused on ambulatory blood pressure measurements (2), which we thought were scientifically valid because (a) the number of patients in whom ambulatory blood pressure monitoring could be performed was rather large; (b) patients' age extended to the so-called "old-elderly" range, in which information on ambulatory blood pressure changes during antihypertensive treatment is still limited; and (c) ambulatory blood pressure is substantially devoid of a placebo effect. On this crucial third point, we disagree with Professor Bulpitt's considerations. There is now a large body of evidence that, unlike clinic blood pressure, 24-h, daytime, and nighttime average blood pressures are not significantly less when placebo is administered for weeks or months (3,4). It is also clear that the data from Staessen et al. (5) should not be interpreted as at variance with these results. One, in the study by Staessen et al. (5), the "placebo" patients showed a reduction in 24-h average systolic blood pressure that was not only small (2.4 mm Hg) but also about a third the concomitant reduction in clinic systolic blood pressure (6.6 mm Hg). Two, whereas in the placebo group, clinic diastolic blood pressure was significantly reduced (1.4 mm Hg), ambulatory diastolic blood pressure was not. Three, and most important, in the study by Staessen et al. (5) statistically significant blood pressure reductions were seen only after administration of placebo for 1 year. This makes the results somewhat irrelevant for antihypertensive drug studies, in which only short- or medium-term placebo administration is ethically acceptable. It also makes interpretation of the data difficult because it is conceivable that in elderly patients with systolic hypertension [i.e., the patients involved in the study by Staessen et al. (5)], a small long-term reduction in systolic blood pressure is caused by a decline in cardiac function. We have also some reservations on Professor Bulpitt's definition of a "controlled" study. To us this does not mean that a study has to answer all or most of the important points concerning an issue, but that its design allows the results to be interpreted according to the original hypothesis, even if single and simple. For us the hypothesis was whether a combination of a low-dose thiazide and an ACE inhibitor (a treatment largely used as first line in the clinical practice) effectively reduced blood pressure over the 24 h in aged patients (i.e., in patients in whom suboptimal or undesirable blood pressure effects of treatment cannot be easily excluded). We believe our study allowed this to be obtained. It did not allow, of course, determination of the role of the combination components in the ambulatory blood pressure effect, an interesting question that would have required, as Professor Bulpitt emphasizes, a parallel design involving three groups of patients or a cross-over design on a single group of patients studied with the three different treatments.

Patients with resistant hypertension (RH) are at greater risk for stroke, renal insufficiency, and cardiovascular disease (CVD) events than are those for whom blood pressure (BP) is responsive to and well controlled by therapeutic interventions. Although all chronotherapy trials have compared the effects on BP regulation of full daily doses of medications when ingested in the morning versus at bedtime, prescription of the same medications in divided doses twice daily (BID) is frequent. Here, we investigated the influence of hypertension treatment-time regimen on the circadian BP pattern, degree of BP control, and relevant clinical and laboratory medicine parameters of RH patients evaluated by 48-h ambulatory BP monitoring (ABPM). This cross-sectional study evaluated 2899 such patients (1701 men/1198 women), 64.2 ± 11.8 (mean ± SD) yrs of age, enrolled in the Hygia Project. Among the participants, 1084 were ingesting all hypertension medications upon awakening (upon-awakening regimen), 1436 patients were ingesting the full daily dose of ≥1 of them at bedtime (bedtime regimen), and 379 were ingesting split doses of ≥1 medications BID upon awakening and at bedtime (BID regimen). Patients of the bedtime regimen compared with the other two treatment-time regimens had lower likelihood of microalbuminuria and chronic kidney disease; significantly lower albumin/creatinine ratio, glucose, total cholesterol, and low-density lipoprotein (LDL) cholesterol; plus higher estimated glomerular filtration rate and high-density lipoprotein (HDL) cholesterol. The bedtime regimen was also significantly associated with lower asleep systolic (SBP) and diastolic (DBP) BP means than the upon-awakening and BID regimens. The sleep-time relative SBP and DBP decline was significantly attenuated by the upon-awakening and BID regimens (p < .001), resulting in significantly higher prevalence of non-dipping in these two treatment-time regimen groups (80.5% and 77.3%, respectively) than in the bedtime regimen (54.4%; p < .001 between groups). Additionally, the prevalence of the riser BP pattern, associated with highest CVD risk, was much greater, 31.0% and 29.8%, respectively, among patients of the upon-awakening and BID-treatment regimens, compared with the bedtime regimen (17.6%; p < .001 between groups). Patients of the bedtime regimen also showed significantly higher prevalence of properly controlled ambulatory BP (p < .001) as a result of a greater proportion of them showing complete control of asleep SBP and DBP means. Our findings demonstrate significantly lower asleep SBP and DBP means and attenuated prevalence of blunted nighttime BP decline, i.e., lower prevalence of CVD risk markers, in RH patients ingesting the full daily dose of ≥1 hypertension medications at bedtime than in those ingesting all of them upon awakening or ≥1 of them as split doses BID. In RH, ingesting the same medications BID neither improves ambulatory BP control nor reduces the prevalence of non-dipping, and cannot be considered chronotherapy. Collectively, findings of this study indicate that a bedtime hypertension medication regimen, in conjunction with proper patient evaluation by ABPM to corroborate the diagnosis of true RH and avoid treatment-induced nocturnal hypotension, should be the therapeutic scheme of choice for patients who, by conventional cuff methods (and in the absence of ABPM) and the morning-treatment regimen, have been mistakenly judged to be resistant to therapy. (Author correspondence: rhermida@uvigo.es)