Office measurement vs. ambulatory blood pressure monitoring: associations with mortality in patients with or without diabetes.

BACKGROUND AND AIMS: Guidelines suggest similar blood pressure (BP) targets in patients with and without diabetes and recommend ambulatory BP monitoring (ABPM) to diagnose and classify hypertension. It was explored whether different levels of ambulatory and office BP and different hypertension phenotypes associate with differences of risk in diabetes and no diabetes. METHODS: This analysis assessed outcome data from the Spanish ABPM Registry in 59 124 patients with complete available data. The associations between office, mean, daytime, and nighttime ambulatory BP with the risk in patients with or without diabetes were explored. The effects of diabetes on mortality in different hypertension phenotypes, i.e. sustained hypertension, white-coat hypertension, and masked hypertension, compared with normotension were studied. Analyses were done with Cox regression analyses and adjusted for demographic and clinical confounders. RESULTS: A total of 59 124 patients were recruited from 223 primary care centres in Spain. The majority had an office systolic BP >140 mmHg (36 700 patients), and 23 128 (40.6%) patients were untreated. Diabetes was diagnosed in 11 391 patients (19.2%). Concomitant cardiovascular (CV) disease was present in 2521 patients (23.1%) with diabetes and 4616 (10.0%) without diabetes. Twenty-four-hour mean, daytime, and nighttime ambulatory BP were associated with increased risk in diabetes and no diabetes, while in office BP, there was no clear association with no differences with and without diabetes. While the relative association of BP to CV death risk was similar in diabetes compared with no diabetes (mean interaction P = .80, daytime interaction P = .97, and nighttime interaction P = .32), increased event rates occurred in diabetes for all ABPM parameters for CV death and all-cause death. White-coat hypertension was not associated with risk for CV death (hazard ratio 0.86; 95% confidence interval 0.72-1.03) and slightly reduced risk for all-cause death in no diabetes (hazard ratio 0.89; confidence interval 0.81-0.98) but without significant interaction between diabetes and no diabetes. Sustained hypertension and masked hypertension in diabetes and no diabetes were associated with even higher risk. There were no significant interactions in hypertensive phenotypes between diabetes and no diabetes and CV death risk (interaction P = .26), while some interaction was present for all-cause death (interaction P = .043) and non-CV death (interaction P = .053). CONCLUSIONS: Diabetes increased the risk for all-cause death, CV, and non-CV death at every level of office and ambulatory BP. Masked and sustained hypertension confer to the highest risk, while white-coat hypertension appears grossly neutral without interaction of relative risk between diabetes and no diabetes. These results support recommendations of international guidelines for strict BP control and using ABPM for classification and assessment of risk and control of hypertension, particularly in patients with diabetes. CLINICAL TRIAL REGISTRATION: Not applicable.

Relationship between clinic and ambulatory blood pressure and mortality: an observational cohort study in 59 124 patients.

BACKGROUND: Ambulatory blood pressure provides a more comprehensive assessment than clinic blood pressure, and has been reported to better predict health outcomes than clinic or home pressure. We aimed to examine associations of clinic and 24-h ambulatory blood pressure with all-cause and cardiovascular mortality in a large cohort of primary care patients referred for assessment of hypertension. METHODS: We did an observational cohort study using clinic and ambulatory blood pressure data obtained from March 1, 2004, to Dec 31, 2014, from the Spanish Ambulatory Blood Pressure Registry. This registry included patients from 223 primary care centres from the Spanish National Health System in all 17 regions of Spain. Mortality data (date and cause) were ascertained by a computerised search of the vital registry of the Spanish National Institute of Statistics. Complete data were available for age, sex, all blood pressure measures, and BMI. For each study participant, follow-up was from the date of their recruitment to the date of death or Dec 31, 2019, whichever occurred first. Cox models were used to estimate associations between usual clinic or ambulatory blood pressure and mortality, adjusted for confounders and additionally for alternative measures of blood pressure. For each measure of blood pressure, we created five groups (ie, fifths) defined by quintiles of that measure among those who subsequently died. FINDINGS: During a median follow-up of 9·7 years, 7174 (12·1%) of 59 124 patients died, including 2361 (4·0%) from cardiovascular causes. J-shaped associations were observed for several blood pressure measures. Among the top four baseline-defined fifths, 24-h systolic blood pressure was more strongly associated with all-cause death (hazard ratio [HR] 1·41 per 1 - SD increment [95% CI 1·36-1·47]) than clinic systolic blood pressure (1·18 [1·13-1·23]). After adjustment for clinic blood pressure, 24-h blood pressure remained strongly associated with all-cause deaths (HR 1·43 [95% CI 1·37-1·49]), but the association between clinic blood pressure and all-cause death was attenuated when adjusted for 24-h blood pressure (1·04 [1·00-1·09]). Compared with the informativeness of clinic systolic blood pressure (100%), night-time systolic blood pressure was most informative about risk of all-cause death (591%) and cardiovascular death (604%). Relative to blood pressure within the normal range, elevated all-cause mortality risks were observed for masked hypertension (HR 1·24 [95% CI 1·12-1·37]) and sustained hypertension (1·24 [1·15-1·32]), but not white-coat hypertension, and elevated cardiovascular mortality risks were observed for masked hypertension (1·37 [1·15-1·63]) and sustained hypertension (1·38 [1·22-1·55]), but not white-coat hypertension. INTERPRETATION: Ambulatory blood pressure, particularly night-time blood pressure, was more informative about the risk of all-cause death and cardiovascular death than clinic blood pressure. FUNDING: Spanish Society of Hypertension, Lacer Laboratories, UK Medical Research Council, Health Data Research UK, National Institute for Health and Care Research Biomedical Research Centres (Oxford and University College London Hospitals), and British Heart Foundation Centre for Research Excellence.

Donor-Dependent Variations in Systemic Oxidative Stress and Their Association with One-Year Graft Outcomes in Kidney Transplantation.

INTRODUCTION: Oxidative stress has been implicated in complications after kidney transplantation (KT), including delayed graft function (DGF) and rejection. However, its role in long-term posttransplant outcomes remains unclear. METHODS: We investigated oxidative damage and antioxidant defense dynamics, and their impact on the graft outcomes, in 41 KT recipients categorized by type of donation over 12 months. Oxidative status was determined using OxyScore and AntioxyScore indexes, which comprise several circulating biomarkers of oxidative damage and antioxidant defense. Donor types included donation after brain death (DBD [61.0%]), donation after circulatory death (DCD [26.8%]), and living donation (LD [12.1%]). RESULTS: There was an overall increase in oxidative damage early after transplantation, which was significantly higher in DCD as compared to DBD and LD recipients. The multivariate adjustment confirmed the independent association of OxyScore and type of deceased donation with DGF, donor kidney function, and induction therapy with antithymocyte globulin. There were no differences in terms of antioxidant defense. Lower oxidative damage at day 7 predicted better graft function at 1-year posttransplant only in DBD recipients. CONCLUSION: DCD induced greater short-term oxidative damage after KT, whereas the early levels of oxidative damage were predictive of the graft function 1 year after KT among DBD recipients.

Targeting the TWEAK-Fn14 pathway prevents dysfunction in cardiac calcium handling after acute kidney injury.

Heart and kidney have a closely interrelated pathophysiology. Acute kidney injury (AKI) is associated with significantly increased rates of cardiovascular events, a relationship defined as cardiorenal syndrome type 3 (CRS3). The underlying mechanisms that trigger heart disease remain, however, unknown, particularly concerning the clinical impact of AKI on cardiac outcomes and overall mortality. Tumour necrosis factor-like weak inducer of apoptosis (TWEAK) and its receptor fibroblast growth factor-inducible 14 (Fn14) are independently involved in the pathogenesis of both heart and kidney failure, and recent studies have proposed TWEAK as a possible therapeutic target; however, its specific role in cardiac damage associated with CRS3 remains to be clarified. Firstly, we demonstrated in a retrospective longitudinal clinical study that soluble TWEAK plasma levels were a predictive biomarker of mortality in patients with AKI. Furthermore, the exogenous application of TWEAK to native ventricular cardiomyocytes induced relevant calcium (Ca2+ ) handling alterations. Next, we investigated the role of the TWEAK-Fn14 axis in cardiomyocyte function following renal ischaemia-reperfusion (I/R) injury in mice. We observed that TWEAK-Fn14 signalling was activated in the hearts of AKI mice. Mice also showed significantly altered intra-cardiomyocyte Ca2+ handling and arrhythmogenic Ca2+ events through an impairment in sarcoplasmic reticulum Ca2+ -adenosine triphosphatase 2a pump (SERCA2a ) and ryanodine receptor (RyR2 ) function. Administration of anti-TWEAK antibody after reperfusion significantly improved alterations in Ca2+ cycling and arrhythmogenic events and prevented SERCA2a and RyR2 modifications. In conclusion, this study establishes the relevance of the TWEAK-Fn14 pathway in cardiac dysfunction linked to CRS3, both as a predictor of mortality in patients with AKI and as a Ca2+ mishandling inducer in cardiomyocytes, and highlights the cardioprotective benefits of TWEAK targeting in CRS3. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

The Urinary Glycopeptide Profile Differentiates Early Cardiorenal Risk in Subjects Not Meeting Criteria for Chronic Kidney Disease.

Early diagnosis and treatment of chronic kidney disease (CKD) is a worldwide challenge. Subjects with albumin-to-creatinine ratio (ACR) ≥ 30 mg/g and preserved renal function are considered to be at no cardiorenal risk in clinical practice, but prospective clinical studies evidence increased risk, even at the high-normal (HN) ACR range (10-30 mg/g), supporting the need to identify other molecular indicators for early assessment of patients at higher risk. Following our previous studies, here we aim to stratify the normoalbuminuria range according to cardiorenal risk and identify the glycoproteins and N-glycosylation sites associated with kidney damage in subclinical CKD. Glycoproteins were analyzed in urine from hypertensive patients within the HN ACR range compared to control group (C; ACR < 10 mg/g) by mass spectrometry. A different cohort was analyzed for confirmation (ELISA) and sex perspective was evaluated. Patients' follow-up for 8 years since basal urine collection revealed higher renal function decline and ACR progression for HN patients. Differential N-glycopeptides and their N -glycosylation sites were also identified, together with their pathogenicity. N-glycosylation may condition pathological protein deregulation, and a panel of 62 glycoproteins evidenced alteration in normoalbuminuric subjects within the HN range. Haptoglobin-related protein, haptoglobin, afamin, transferrin, and immunoglobulin heavy constant gamma 1 (IGHG1) and 2 (IGHG2) showed increased levels in HN patients, pointing to disturbed iron metabolism and tubular reabsorption and supporting the tubule as a target of interest in the early progression of CKD. When analyzed separately, haptoglobin, afamin, transferrin, and IGHG2 remained significant in HN, in both women and men. At the peptide level, 172 N-glycopeptides showed differential abundance in HN patients, and 26 showed high pathogenicity, 10 of them belonging to glycoproteins that do not show variation between HN and C groups. This study highlights the value of glycosylation in subjects not meeting KDIGO criteria for CKD. The identified N-glycopeptides and glycosylation sites showed novel targets, for both the early assessment of individual cardiorenal risk and for intervention aimed at anticipating CKD progression.

Role of non-alcoholic fatty liver disease in the evolution of renal function in patients with diabetes mellitus.

BACKGROUND: The increasing prevalence of type 2 diabetes mellitus (T2DM) has influenced in an increasing prevalence of chronic kidney disease (CKD). Little is known about the influence of non-alcoholic fatty liver disease (NAFLD) on the progression of CKD. The aim of this study was to analyse the role of NAFLD and its severity in the progression of renal function in patients with T2DM. METHODS: We conducted a retrospective and observational study including patients with T2DM and estimated glomerular filtration rate (eGFR) >30 mL/min/1.73 m2. NAFLD was defined as the presence of compatible ultrasonography and/or the presence of fibrosis using the NAFLD score. Patients were classified into three groups according to the NAFLD score: Group 1: <-1.85; Group 2: -1.85-0.18 and Group 3: >0.18. RESULTS: A total of 102 patients were included [67.6% males, median age 59 years [interquartile range (IQR) 53-64)], with a median time of T2DM evolution of 70 months (IQR 39-131). Group 3 had lower eGFR (84.8 ± 40.4 versus 71.4 ± 30.6 mL/min/1.73 m2; P = 0.03) and higher proteinuria at baseline (0.56 ± 0.77 versus 1.59 ± 2.70 g/24 h; P = 0.05). After a follow-up time of 75.8 ± 23.9 months, Group 3 had a significant decrease in eGFR (66.6 ± 33.3 versus 36.8 ± 23.1 mL/min/1.73 m2; P ≤ 0.01) and a higher risk of CKD progression [odds ratio 7.50 (95% confidence interval 2.76-20.35); P ≤ 0.001] defined as a decrease in eGFR of >50%. CONCLUSIONS: The presence of NAFLD with high-risk fibrosis confers higher risk of CKD progression in patients with T2DM. Therefore NAFLD should be a risk factor evaluated in these patients to optimize treatment.

Relationship between Clinic and Ambulatory Blood-Pressure Measurements and Mortality.

BACKGROUND: Evidence for the influence of ambulatory blood pressure on prognosis derives mainly from population-based studies and a few relatively small clinical investigations. This study examined the associations of blood pressure measured in the clinic (clinic blood pressure) and 24-hour ambulatory blood pressure with all-cause and cardiovascular mortality in a large cohort of patients in primary care. METHODS: We analyzed data from a registry-based, multicenter, national cohort that included 63,910 adults recruited from 2004 through 2014 in Spain. Clinic and 24-hour ambulatory blood-pressure data were examined in the following categories: sustained hypertension (elevated clinic and elevated 24-hour ambulatory blood pressure), "white-coat" hypertension (elevated clinic and normal 24-hour ambulatory blood pressure), masked hypertension (normal clinic and elevated 24-hour ambulatory blood pressure), and normotension (normal clinic and normal 24-hour ambulatory blood pressure). Analyses were conducted with Cox regression models, adjusted for clinic and 24-hour ambulatory blood pressures and for confounders. RESULTS: During a median follow-up of 4.7 years, 3808 patients died from any cause, and 1295 of these patients died from cardiovascular causes. In a model that included both 24-hour and clinic measurements, 24-hour systolic pressure was more strongly associated with all-cause mortality (hazard ratio, 1.58 per 1-SD increase in pressure; 95% confidence interval [CI], 1.56 to 1.60, after adjustment for clinic blood pressure) than the clinic systolic pressure (hazard ratio, 1.02; 95% CI, 1.00 to 1.04, after adjustment for 24-hour blood pressure). Corresponding hazard ratios per 1-SD increase in pressure were 1.55 (95% CI, 1.53 to 1.57, after adjustment for clinic and daytime blood pressures) for nighttime ambulatory systolic pressure and 1.54 (95% CI, 1.52 to 1.56, after adjustment for clinic and nighttime blood pressures) for daytime ambulatory systolic pressure. These relationships were consistent across subgroups of age, sex, and status with respect to obesity, diabetes, cardiovascular disease, and antihypertensive treatment. Masked hypertension was more strongly associated with all-cause mortality (hazard ratio, 2.83; 95% CI, 2.12 to 3.79) than sustained hypertension (hazard ratio, 1.80; 95% CI, 1.41 to 2.31) or white-coat hypertension (hazard ratio, 1.79; 95% CI, 1.38 to 2.32). Results for cardiovascular mortality were similar to those for all-cause mortality. CONCLUSIONS: Ambulatory blood-pressure measurements were a stronger predictor of all-cause and cardiovascular mortality than clinic blood-pressure measurements. White-coat hypertension was not benign, and masked hypertension was associated with a greater risk of death than sustained hypertension. (Funded by the Spanish Society of Hypertension and others.).

Urinary alpha-1 antitrypsin and CD59 glycoprotein predict albuminuria development in hypertensive patients under chronic renin-angiotensin system suppression.

BACKGROUND: Hypertension is a multi-factorial disease of increasing prevalence and a major risk factor for cardiovascular mortality even in the presence of adequate treatment. Progression of cardiovascular disease (CVD) occurs frequently during chronic renin-angiotensin-system (RAS) suppression, and albuminuria is a marker of CV risk. High prevalence of albuminuria in treated hypertensive patients has been demonstrated, but there are no available markers able to predict evolution. The aim of this study was the identification of novel indicators of albuminuria progression measurable in urine of diabetic and non-diabetic patients. METHODS: 1143 hypertensive patients under chronic treatment were followed for a minimum period of 3 years. Among them, 105 diabetic and non-diabetic patients were selected and classified in three groups according to albuminuria development during follow-up: (a) patients with persistent normoalbuminuria; (b) patients developing de novo albuminuria; (c) patients with maintained albuminuria. Differential urine analysis was performed by 2D gel electrophoresis (2D-DIGE) and further confirmed by liquid chromatography-mass spectrometry. Non-parametric statistical tests were applied. RESULTS: CD59 glycoprotein and alpha-1 antitrypsin (AAT) resulted already altered in patients developing albuminuria de novo, with a similar response in those with maintained albuminuria. A prospective study in a sub-group of normoalbuminuric patients who were clinically followed up for at least 1 year from urine sampling, revealed CD59 and AAT proteins significantly varied in the urine collected from normoalbuminurics who will negatively progress, serving as predictors of future albuminuria development. CONCLUSIONS: CD59 and AAT proteins are significantly altered in hypertensive patients developing albuminuria. Interestingly, CD59 and AAT are able to predict, in normoalbuminuric individuals, who will develop albuminuria in the future, being potential predictors of vascular damage and CV risk. These findings contribute to early identify patients at risk of developing albuminuria even when this classical predictor is still in the normal range, constituting a novel strategy towards a prompt and more efficient therapeutic intervention with better outcome.

Ambulatory blood pressure monitoring in daily clinical practice - the Spanish ABPM Registry experience.

Many patients are hypertensive at the medical settings but show normal blood pressure out of the doctor's office, and are classified as white-coat hypertensives. On the other hand, many patients with controlled hypertension at the clinic show ambulatory blood pressure levels above the thresholds considered for an adequate blood pressure control, known as having masked hypertension. Using data from the Spanish Ambulatory Blood Pressure Monitoring Registry (Spanish ABPM Registry), a national program developed to promote the use of the ambulatory technique for hypertension management in daily practice, we have reviewed the main strengths of this approach, that is the ability to detect discrepancies of blood pressure status with respect to office blood pressure measurement, and to better assess accurate rates of hypertension control. White-coat hypertension within patients with elevated office blood pressure, and masked hypertension within office-controlled patients affected one of three patients in each office status. On the other hand, rates of ambulatory blood pressure control (50%) doubled those of office blood pressure control (25%), still remaining half the patients uncontrolled. We think that a systematic use of ambulatory blood pressure monitoring, and strategies to improve blood pressure control constitute key priorities in hypertension management.

Role of matrix metalloproteinase-9 in chronic kidney disease: a new biomarker of resistant albuminuria.

Resistant albuminuria, developed under adequate chronic blockade of the renin-angiotensin system, is a clinical problem present in a small number of patients with chronic kidney disease (CKD). The mechanism underlying this resistant albuminuria remains unknown. Matrix metalloproteinases (MMPs) are involved in the pathophysiology of cardiovascular and renal diseases. In the present study we tested the role of MMPs in resistant albuminuria. First we evaluated gelatinase MMP-2 and MMP-9 activity by zymography in the Munich Wistar Frömter (MWF) rat, a model of progressive albuminuria, and subsequently in patients with resistant albuminuria. Markers of oxidative stress were observed in the kidneys of MWF rats, together with a significant increase in pro-MMP-2 and active MMP-9 forms. These changes were normalized together with reduced albuminuria in consomic MWF-8(SHR) rats, in which chromosome 8 of MWF was replaced with the respective chromosome from spontaneously hypertensive rats. The MMP-2 and MMP-9 protein levels were similar in patients with normal and resistant albuminuria; however, high circulating levels of collagen IV, a specific biomarker of tissue collagen IV degradation, were observed in patients with resistant albuminuria. These patients showed a significant increase in gelatinase MMP-2 and MMP-9 activity, but only a significant increase in the active MMP-9 form quantified by ELISA, which correlated significantly with the degree of albuminuria. Although the expression of the tissue inhibitor of MMP-9 (TIMP)-1 was similar, a novel AlphaLISA assay demonstrated that the MMP-9-TIMP-1 interaction was reduced in patients with resistant albuminuria. It is of interest that oxidized TIMP-1 expression was higher in patients with resistant albuminuria. Therefore, increased circulating MMP-9 activity is associated with resistant albuminuria and a deleterious oxidative stress environment appears to be the underlying mechanism. These changes might contribute to the progression of CKD in these patients.

Office and ambulatory blood pressure control in hypertensive patients treated with different two-drug and three-drug combinations.

There is scarce information regarding ambulatory blood pressure (BP) achieved in daily practice with a wide range of antihypertensive drug combinations. We looked for differences in office and ambulatory BP among major drug combinations of two and three antihypertensive agents from a different drugs class. A total of 17187 patients treated with six types of two-drug combinations and 9724 treated with six types of three-drug combinations from the Spanish ABPM Registry were analyzed. We compared achieved office and ambulatory BP, as well as office (< 140/90 mmHg) and ambulatory (24-hour BP < 130/80; day BP < 135/85, and night BP < 120/70 mmHg) BP control among groups. The combination of renin-angiotensin system (RAS) blockers with diuretics and the triple combination of RAS blockers with diuretics and calcium channel blockers (CCB) were associated with lower values of 24-hour, daytime and nighttime BP, as well as more pronounced nocturnal BP dip. Compared with such combinations (reference), other double combinations had lower rates of ambulatory BP control. Moreover, triple combinations containing alpha blockers also had lower rates of ambulatory BP control. We conclude that even with similar office BP control, differences exist among antihypertensive two-drug and three-drug combinations with respect to ambulatory BP control achieved during treatment, with RAS blockers/diuretics and RAS blockers/CCBs/diuretics obtaining better control rates. This can help physicians choose among drug combinations in order to obtain further ambulatory BP reductions.

High prevalence of masked uncontrolled hypertension in people with treated hypertension.

AIM: There are limited data on the quality of treated blood pressure (BP) control during normal daily life, and in particular, the prevalence of 'masked uncontrolled hypertension' (MUCH) in people with treated and seemingly well-controlled BP is unknown. This is important because masked hypertension in 'treatment naïve' patients is associated with a high risk of cardiovascular events. We therefore conducted the first study to define the prevalence and characteristics of MUCH among a large sample of hypertensive patients in routine clinical practice in whom BP was treated and controlled to recommended clinic BP goals. METHODS AND RESULTS: We analysed data from the Spanish Society of Hypertension ambulatory blood pressure monitoring (ABPM) Registry and identified patients with treated and controlled BP according to current international guidelines (clinic BP <140/90 mmHg). Masked uncontrolled hypertension was diagnosed in these patients if despite controlled clinic BP, the mean 24-h ABPM average remained elevated (24-h systolic BP ≥130 mmHg and/or 24-h diastolic BP ≥80 mmHg). From 62 788 patients with treated BP in the Spanish registry, we identified 14 840 with treated and controlled clinic BP, of whom 4608 patients (31.1%) had MUCH according to 24-h ABPM criteria (mean age 59.4 years, 59.7% men). The prevalence of MUCH was significantly higher in males, patients with borderline clinic BP (130-9/80-9 mmHg), and patients at high cardiovascular risk (smokers, diabetes, obesity). Masked uncontrolled hypertension was most often because of poor control of nocturnal BP, with the proportion of patients in whom MUCH was solely attributable to an elevated nocturnal BP almost double that solely attributable to daytime BP elevation (24.3 vs. 12.9%, P < 0.001). CONCLUSION: The prevalence of masked suboptimal BP control in patients with treated and well-controlled clinic BP is high. Clinic BP monitoring alone is thus inadequate to optimize BP control because many patients have an elevated nocturnal BP. These findings suggest that ABPM should become more routine to confirm BP control, especially in higher risk groups and/or those with borderline control of clinic BP.

Usefulness of ambulatory blood pressure monitoring (ABPM) in daily clinical practice: Data from the Spanish ABPM registry.

1. Hypertension is one of the most important challenges for public health systems because of its high prevalence and its association with the risk of cardiovascular and renal diseases. 2. Adequate control of hypertension is low in population and medical settings, with physicians frequently misclassifying patients' blood pressure status based on readings taken in the clinic rather than ambulatory blood pressure measurements (ABPM). 3. Data from the Spanish Society of Hypertension ABPM registry support ABPM as a feasible option in the primary care setting, providing valuable information for the diagnosis and management of hypertension. By using ABPM rather than office BP monitoring, BP control can be doubled. This is an encouraging message to clinicians, although there is still a relatively large degree of undetected controlled and uncontrolled hypertension. 4. This short review describes the design, development and main results of the Spanish Society of Hypertension ABPM registry, a project based on a large-scale network of Spanish physicians trained in ABPM.

Impact of timing of antihypertensive treatment on mortality: an observational study from the Spanish Ambulatory Blood Pressure Monitoring Registry.

BACKGROUND AND AIMS: Whether bedtime versus morning administration of antihypertensive therapy is beneficial on outcomes is controversial. We evaluated the risk of total and cardiovascular mortality in a very large observational cohort of treated hypertensive patients, according to the timing of their usual treatment administration (morning versus evening). METHODS: Vital status and cause of death were obtained from death certificates of 28 406 treated hypertensive patients (mean age 62 years, 53% male individuals), enrolled in the Spanish Ambulatory Blood Pressure Monitoring (ABPM) Registry between 2004 and 2014. Among the 28 406 patients, most (86%) received their medication exclusively in the morning; whilst 13% were treated exclusively in the evening or at bedtime. Follow-up was for a median of 9.7 years and 4345 deaths occurred, of which 1478 were cardiovascular deaths. RESULTS: Using Cox-models adjusted for clinical confounders and 24-h SBP, and compared with patients treated in the morning (reference group), all-cause mortality [hazard ratio 1.01; 95% CI 0.93-1.09) and cardiovascular mortality (hazard ratio 1.04; 95% CI 0.91-1.19) was not significantly different in those receiving evening medication dosing. The results were consistent in all the subgroups of patients analysed. CONCLUSION: In this very large observational study, morning versus bedtime dosing of antihypertensive medication made no difference to the subsequent risk of all-cause or cardiovascular mortality. These findings are in accordance with results from a recent randomized controlled trial and do not support the hypothesis of a specific beneficial effect of night-time antihypertensive treatment dosing on risk of all-cause or cardiovascular death.

A blunted nocturnal blood pressure decline is associated with all-cause and cardiovascular mortality.

OBJECTIVE: It has been suggested that a blunted nocturnal blood pressure (BP) decline is associated with a poor prognosis. Nevertheless, it remains unclear if an abnormal dipping is deleterious per se or it merely reflects an elevated BP during sleep. We aimed to assess the prognostic value of nocturnal BP decline, with or without concomitant elevated nocturnal BP. METHODS: Vital status and cause of death were obtained from death certificates in 59 124 patients, enrolled in the Spanish ABPM Registry between 2004 and 2014 (median follow-up: 10 years). The association between night-to-day ratio (NDR) and dipping patterns (extreme dippers, dippers, reduced dippers, and risers) with all-cause and cardiovascular mortality were evaluated by Cox-proportional models adjusted for clinical confounders and 24 h blood pressure. RESULTS: NDR was associated with all-cause mortality [hazard ratio for 1SD change: 1.15; 95% confidence interval (CI) 1.13-1.17]. Reduced dippers (1.13; 1.06-1.20) and risers (1.41; 1.32-1.51) were associated with an increased risk of all-cause death, whereas extreme dippers (0.90; 0.79-1.02) were not. Elevated NDR (≥0.9) in the absence of elevated night SBP (<120 mmHg) was associated with an increased risk of death (1.13; 1.04-1.22), as well as elevated night SBP but normal NDR (1.38; 1.26-1.50), and the combination of both abnormalities (1.56; 1.46-1.66). Similar results were obtained for cardiovascular mortality. CONCLUSION: Abnormalities in the circadian pattern are associated with an increased risk of all-cause and cardiovascular mortality. This is maintained even in the absence of nocturnal BP elevation.

Resistant Hypertension and Mortality: An Observational Cohort Study.

BACKGROUND: Resistant hypertension is characterized by elevated blood pressure (BP) despite using 3 antihypertensive agents. Ambulatory BP monitoring (ABPM) detects the presence of white-coat resistant hypertension (24-hour BP <130/80 mm Hg). The aim of the study was to evaluate risks of death in resistant hypertension compared with controlled hypertension, as well as in ABPM-confirmed (24-hour BP ≥130 or 80 mm Hg), versus white-coat resistant hypertension. METHODS: We selected 8146 patients with controlled hypertension (office BP <140/90 mm Hg while being treated with ≤3 antihypertensive drugs) and 8577 with resistant hypertension (BP ≥140 or ≥90 mm Hg while being treated with ≥3 drugs). All-cause and cardiovascular mortalities (median follow-up, 9.7 years) were compared between groups, as well as between patients with white-coat (3289) and ABPM-confirmed (5288) resistant hypertension. Hazard ratios (HRs) from Cox models after adjustment for clinical confounders were used for comparisons. RESULTS: Compared with controlled hypertension, resistant hypertension was associated with an increased risk in all-cause (HR, 1.21 [95% CI, 1.12-1.30]) and cardiovascular mortalities (HR, 1.33 [95% CI, 1.17-1.51]) in confounder-adjusted models. Compared with white-coat, ABPM-confirmed resistant hypertension was associated with an increased risk of all-cause (HR, 1.45 [95% CI, 1.32-1.60]) and cardiovascular (HR, 1.68 [95% CI, 1.43-1.98]) mortalities. When ABPM-confirmed and white-coat resistant hypertension were separately compared with controlled hypertension, only the former was associated with an increased risk of death and cardiovascular death (HR, 1.36 [95% CI, 1.26-1.48] and 1.56 [95% CI, 1.36-1.79]), respectively. CONCLUSIONS: ABPM-confirmed resistant hypertension is associated with an increased risk of death and cardiovascular death with respect to both controlled hypertension and white-coat resistant hypertension.

Prognostic Relevance of Short-Term Blood Pressure Variability. The Spanish ABPM Registry.

BACKGROUND: The prognostic relevance of short-term blood pressure (BP) variability in hypertension is not clearly established. We aimed to evaluate the association of short-term BP variability, with all-cause and cardiovascular mortality in a large cohort of patients with hypertension. METHODS: We selected 59 124 patients from the Spanish Ambulatory Blood Pressure Monitoring Registry from 2004 to 2014 (median follow-up: 9.7 years). Systolic and diastolic BP SD and coefficient of variation from daytime and nighttime, weighted SD, weighted coefficient of variation, average real variability (mean of differences between consecutive readings), and BP variability ratio (ratio between systolic and diastolic 24-hour SD) were calculated through baseline 24-hour ambulatory BP monitoring. Association with all-cause and cardiovascular mortality were assessed by Cox regression models adjusted for clinical confounders and BP. RESULTS: Patients who died during follow-up had higher values of BP variability compared with those remaining alive. In adjusted models systolic and diastolic daytime and weighted SD and coefficient of variation, average real variability, as well as systolic nighttime SD and BP variability ratio were all significantly associated with all-cause and cardiovascular mortality. Hazard ratios for 1-SD increase in the systolic components ranged from 1.05 to 1.12 for all-cause mortality and from 1.07 to 1.17 for cardiovascular mortality. A daytime SD≥13 mm Hg, a nighttime and a weighted SD≥12 mm Hg, and an average real variability ≥10 mm Hg, all systolic, were independently associated with mortality. CONCLUSIONS: Short-term blood pressure variability shows a relatively weak but significant association with all-cause and cardiovascular mortality in patients with hypertension.

Urinary extracellular vesicles as a monitoring tool for renal damage in patients not meeting criteria for chronic kidney disease.

Background: Current definition of chronic kidney disease (CKD) identifies only advanced stages, but effective management demands early detection. Urinary albumin-to-creatinine ratio (ACR) 30 mg/g is a cut-off point for CKD clinical diagnosis. Patients with lower values (normoalbuminuria) and eGFR > 60 mL/min/1.73 m2 are considered at no increased cardiorenal risk. However, higher incidence of renal function decline and cardiovascular events have been shown within the normoalbuminuria range. Novel subclinical indicators may help to identify higher-risk patients. Urinary extracellular vesicles (uEVs) are sentinels of renal function non-invasively. Here we aimed to approach the early assessment of cardiorenal risk by investigating the protein cargo of uEVs. Methods: Hypertensive patients were classified in control group (C) with ACR < 10 mg/g, and high-normal group (HN) with ACR 10-30 mg/g. Isolated uEVs were characterized by western blotting and electron microscopy and the protein cargo was analyzed by untargeted proteomics (LC-MS/MS) in a first discovery cohort. Protein confirmation was performed in a different cohort by ExoView. Immunohistochemistry of human kidney biopsies was also performed to evaluate the potential of uEVs to reflect renal damage. Results: HN albuminuria does not affect the uEVs concentration, size, or tetraspanin profile. Among >6200 uEVs proteins identified, 43 define a panel significantly altered in HN patients without variation in urine, mostly annotated in the tubule (39 out of 43). The tubular transporter long-chain fatty acid transport protein 2 (SLC27A2) and the apical membrane protein amnionless (AMN) confirmed their alteration in HN patients evidencing impaired tubular reabsorption. SLC27A2 showed tubular expression and significantly reduced levels in patients with diagnostic criteria for CKD. Conclusions: Alterations in the EV-mediated molecular profile are evident before pathological ACR levels are reached. Direct quantitation of SLC27A2 and AMN in uEVs helps identifying normoalbuminuric subjects with higher cardiorenal risk in early monitoring of CKD.