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Shift work is a risk factor for hypertension, inflammation, and cardiovascular disease. This increased risk cannot be fully explained by classic risk factors. One of the key features of shift workers is that their behavioral and environmental cycles are typically misaligned relative to their endogenous circadian system. However, there is little information on the impact of acute circadian misalignment on cardiovascular disease risk in humans. Here we show—by using two 8-d laboratory protocols—that short-term circadian misalignment (12-h inverted behavioral and environmental cycles for three days) adversely affects cardiovascular risk factors in healthy adults. Circadian misalignment increased 24-h systolic blood pressure (SBP) and diastolic blood pressure (DBP) by 3.0 mmHg and 1.5 mmHg, respectively. These results were primarily explained by an increase in blood pressure during sleep opportunities (SBP, +5.6 mmHg; DBP, +1.9 mmHg) and, to a lesser extent, by raised blood pressure during wake periods (SBP, +1.6 mmHg; DBP, +1.4 mmHg). Circadian misalignment decreased wake cardiac vagal modulation by 8–15%, as determined by heart rate variability analysis, and decreased 24-h urinary epinephrine excretion rate by 7%, without a significant effect on 24-h urinary norepinephrine excretion rate. Circadian misalignment increased 24-h serum interleukin-6, C-reactive protein, resistin, and tumor necrosis factor-α levels by 3–29%. We demonstrate that circadian misalignment per se increases blood pressure and inflammatory markers. Our findings may help explain why shift work increases hypertension, inflammation, and cardiovascular disease risk.

In this phase 1 study involving persons with hypertension, zilebesiran (an RNA interference therapeutic agent) was associated with decreases in angiotensin levels and systolic and diastolic blood pressure.

AbstractObjectiveThe HOME BP (Home and Online Management and Evaluation of Blood Pressure) trial aimed to test a digital intervention for hypertension management in primary care by combining self-monitoring of blood pressure with guided self-management.DesignUnmasked randomised controlled trial with automated ascertainment of primary endpoint.Setting76 general practices in the United Kingdom.Participants622 people with treated but poorly controlled hypertension (>140/90 mm Hg) and access to the internet.InterventionsParticipants were randomised by using a minimisation algorithm to self-monitoring of blood pressure with a digital intervention (305 participants) or usual care (routine hypertension care, with appointments and drug changes made at the discretion of the general practitioner; 317 participants). The digital intervention provided feedback of blood pressure results to patients and professionals with optional lifestyle advice and motivational support. Target blood pressure for hypertension, diabetes, and people aged 80 or older followed UK national guidelines.Main outcome measuresThe primary outcome was the difference in systolic blood pressure (mean of second and third readings) after one year, adjusted for baseline blood pressure, blood pressure target, age, and practice, with multiple imputation for missing values.ResultsAfter one year, data were available from 552 participants (88.6%) with imputation for the remaining 70 participants (11.4%). Mean blood pressure dropped from 151.7/86.4 to 138.4/80.2 mm Hg in the intervention group and from 151.6/85.3 to 141.8/79.8 mm Hg in the usual care group, giving a mean difference in systolic blood pressure of −3.4 mm Hg (95% confidence interval −6.1 to −0.8 mm Hg) and a mean difference in diastolic blood pressure of −0.5 mm Hg (−1.9 to 0.9 mm Hg). Results were comparable in the complete case analysis and adverse effects were similar between groups. Within trial costs showed an incremental cost effectiveness ratio of £11 ($15, €12; 95% confidence interval £6 to £29) per mm Hg reduction.ConclusionsThe HOME BP digital intervention for the management of hypertension by using self-monitored blood pressure led to better control of systolic blood pressure after one year than usual care, with low incremental costs. Implementation in primary care will require integration into clinical workflows and consideration of people who are digitally excluded.Trial registrationISRCTN13790648.

Periods of fasting and refeeding may reduce cardiometabolic risk elevated by Western diet. Here we show in the substudy of NCT02099968, investigating the clinical parameters, the immunome and gut microbiome exploratory endpoints, that in hypertensive metabolic syndrome patients, a 5-day fast followed by a modified Dietary Approach to Stop Hypertension diet reduces systolic blood pressure, need for antihypertensive medications, body-mass index at three months post intervention compared to a modified Dietary Approach to Stop Hypertension diet alone. Fasting alters the gut microbiome, impacting bacterial taxa and gene modules associated with short-chain fatty acid production. Cross-system analyses reveal a positive correlation of circulating mucosa-associated invariant T cells, non-classical monocytes and CD4 + effector T cells with systolic blood pressure. Furthermore, regulatory T cells positively correlate with body-mass index and weight. Machine learning analysis of baseline immunome or microbiome data predicts sustained systolic blood pressure response within the fasting group, identifying CD8 + effector T cells, Th17 cells and regulatory T cells or Desulfovibrionaceae, Hydrogenoanaerobacterium, Akkermansia , and Ruminococcaceae as important contributors to the model. Here we report that the high-resolution multi-omics data highlight fasting as a promising non-pharmacological intervention for the treatment of high blood pressure in metabolic syndrome patients. Nutritional modification including fasting has been shown to reduce cardiometabolic risk linked to western diet. Here the authors show implementation of fasting resulted in alterations to the intestinal microbiota, and circulating immune cells, improving blood pressure and body weight in patients with metabolic syndrome.

To evaluate the feasibility of free-living walking training in type 2 diabetic patients and to investigate the effects of interval-walking training versus continuous-walking training upon physical fitness, body composition, and glycemic control. Subjects with type 2 diabetes were randomized to a control (n = 8), continuous-walking (n = 12), or interval-walking group (n = 12). Training groups were prescribed five sessions per week (60 min/session) and were controlled with an accelerometer and a heart-rate monitor. Continuous walkers performed all training at moderate intensity, whereas interval walkers alternated 3-min repetitions at low and high intensity. Before and after the 4-month intervention, the following variables were measured: VO(2)max, body composition, and glycemic control (fasting glucose, HbA(1c), oral glucose tolerance test, and continuous glucose monitoring [CGM]). Training adherence was high (89 ± 4%), and training energy expenditure and mean intensity were comparable. VO(2)max increased 16.1 ± 3.7% in the interval-walking group (P < 0.05), whereas no changes were observed in the continuous-walking or control group. Body mass and adiposity (fat mass and visceral fat) decreased in the interval-walking group only (P < 0.05). Glycemic control (elevated mean CGM glucose levels and increased fasting insulin) worsened in the control group (P < 0.05), whereas mean (P = 0.05) and maximum (P < 0.05) CGM glucose levels decreased in the interval-walking group. The continuous walkers showed no changes in glycemic control. Free-living walking training is feasible in type 2 diabetic patients. Continuous walking offsets the deterioration in glycemia seen in the control group, and interval walking is superior to energy expenditure-matched continuous walking for improving physical fitness, body composition, and glycemic control.

We hypothesized acute moderate and drastic reductions in uric acid concentration exert different effects on arterial function in healthy normotensive and hypertensive adults. Thirty‐six adults (aged 58 [55;63] years) with or without primary hypertension participated in a three‐way, randomized, double‐blind, crossover study in which [placebo] and [febuxostat] and [febuxostat and rasburicase] were administered. Febuxostat and rasburicase reduce the uric acid concentration by xanthine oxidoreductase inhibition and uric acid degradation into allantoin, respectively. Endothelial function was assessed in response to acetylcholine, sodium nitroprusside, heating (with and without nitric oxide synthase inhibition) using a laser Doppler imager. Arterial stiffness was determined by applanation tonometry, together with blood pressure, renin–angiotensin system activity, oxidative stress, and inflammation. Uric acid concentration was 5.1 [4.1;5.9], 1.9 [1.2;2.2] and 0.2 [0.2;0.3] mg/dL with [placebo], [febuxostat] and [febuxostat–rasburicase] treatments, respectively (p < 0.0001). Febuxostat improved endothelial response to heat particularly when nitric oxide synthase was inhibited (p < 0.05) and reduced diastolic and mean arterial pressure (p = 0.008 and 0.02, respectively). The augmentation index decreased with febuxostat (ANOVA p < 0.04). Myeloperoxidase activity profoundly decreased with febuxostat combined with rasburicase (p < 0.0001). When uric acid dropped, plasmatic antioxidant capacity markedly decreased, while superoxide dismutase activity increased (p < 0.0001). Other inflammatory and oxidant markers did not differ. Acute moderate hypouricemia encompasses minor improvements in endothelial function, blood pressure, and arterial stiffness. Clinical Trial Registration: NCT03395977, https://clinicaltrials.gov/ct2/show/NCT03395977 Acute moderate hypouricemia encompasses minor improvements in endothelial function, blood pressure, and arterial stiffness.

Uncertainty persists over the effects of blood pressure lowering in acute intracerebral haemorrhage. We aimed to combine individual patient-level data from the two largest randomised controlled trials of blood pressure lowering strategies in patients with acute intracerebral haemorrhage to determine the strength of associations between key measures of systolic blood pressure control and safety and efficacy outcomes. We did a preplanned pooled analysis of individual patient-level data acquired from the main phase of the Intensive Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial (INTERACT2) and the second Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH-II) trial. These trials included adult patients aged 19–99 years with spontaneous (non-traumatic) intracerebral haemorrhage and elevated systolic blood pressure, without a clear indication or contraindication to treatment. Patients were excluded if they had a structural cerebral cause for the intracerebral haemorrhage, had a low score (3–5) on the Glasgow Coma Scale, or required immediate neurosurgery. Our primary analysis assessed the independent associations between three post-randomisation systolic blood pressure summary measures—magnitude of reduction in 1 h, mean achieved systolic blood pressure, and variability in systolic blood pressure between 1 h and 24 h—and the primary outcome of functional status, as defined by the distribution of scores on the modified Rankin Scale at 90 days post-randomisation. We analysed the systolic blood pressure measures as continuous variables using generalised linear mixed models, adjusted for baseline covariables and trial. The primary and safety analyses were done in a modified intention-to-treat population, which only included patients with sufficient data on systolic blood pressure. 3829 patients (mean age 63·1 years [SD 12·9], 1429 [37%] women, and 2490 [65%] Asian ethnicity) were randomly assigned in INTERACT2 and ATACH-II, with a median neurological impairment defined by scores on the National Institutes of Health Stroke Scale of 11 (IQR 6–16) and median time from the onset of symptoms of intracerebral haemorrhage to randomisation of 3·6 h (2·7–4·4). We excluded 20 patients with insufficient or no systolic blood pressure data, and we imputed missing systolic blood pressure data in 23 (1%) of the remaining 3809 patients. Overall, the mean magnitude of early systolic blood pressure reduction was 29 mm Hg (SD 22), and subsequent mean systolic blood pressure achieved was 147 mm Hg (15) and variability in systolic blood pressure was 14 mm Hg (8). Achieved systolic blood pressure was continuously associated with functional status (improvement per 10 mm Hg increase adjusted odds ratio [OR] 0·90 [95% CI 0·87–0·94], p<0·0001). Symptomatic hypotension occurred in 28 (1%) patients, renal serious adverse events occurred in 26 (1%) patients, and cardiac serious adverse events occurred in 99 (3%) patients. Our pooled analyses indicate that achieving early and stable systolic blood pressure seems to be safe and associated with favourable outcomes in patients with acute intracerebral haemorrhage of predominantly mild-to-moderate severity. None.

The SYMPLICITY HTN-3 (Renal Denervation in Patients With Uncontrolled Hypertension) trial showed the safety but not efficacy of the Symplicity system (Medtronic, Santa Rosa, CA, USA) at 6 months follow-up in patients with treatment-resistant hypertension. This final report presents the 36-month follow-up results. SYMPLICITY HTN-3 was a single-blind, multicentre, sham-controlled, randomised clinical trial, done in 88 centres in the USA. Adults aged 18–80 years, with treatment-resistant hypertension on stable, maximally tolerated doses of three or more drugs including a diuretic, who had a seated office systolic blood pressure of 160 mm Hg or more and 24 h ambulatory systolic blood pressure of 135 mm Hg or more were randomly assigned (2:1) to receive renal artery denervation using the single electrode (Flex) catheter or a sham control. The original primary endpoint was the change in office systolic blood pressure from baseline to 6 months for the renal artery denervation group compared with the sham control group. Patients were unmasked after the primary endpoint assessment at 6 months, at which point eligible patients in the sham control group who met the inclusion criteria (office blood pressure ≥160 mm Hg, 24 h ambulatory systolic blood pressure ≥135 mm Hg, and still prescribed three or more antihypertensive medications) could cross over to receive renal artery denervation. Changes in blood pressure up to 36 months were analysed in patients in the original renal artery denervation group and sham control group, including those who underwent renal artery denervation after 6 months (crossover group) and those who did not (non-crossover group). For comparisons between the renal artery denervation and sham control groups, follow-up blood pressure values were imputed for patients in the crossover group using their most recent pre-crossover masked blood pressure value. We report long-term blood pressure changes in renal artery denervation and sham control groups, and investigate blood pressure control in both groups using time in therapeutic blood pressure range analysis. The primary safety endpoint was the incidence of all-cause mortality, end stage renal disease, significant embolic event, renal artery perforation or dissection requiring intervention, vascular complications, hospitalisation for hypertensive crisis unrelated to non-adherence to medications, or new renal artery stenosis of more than 70% within 6 months. The trial is registered with ClinicalTrials.gov, NCT01418261. From Sep 29, 2011, to May 6, 2013, 1442 patients were screened, of whom 535 (37%; 210 [39%] women and 325 [61%] men; mean age 57·9 years [SD 10·7]) were randomly assigned: 364 (68%) patients received renal artery denervation (mean age 57·9 years [10·4]) and 171 (32%) received the sham control (mean age 56·2 years [11·2]). 36-month follow-up data were available for 219 patients (original renal artery denervation group), 63 patients (crossover group), and 33 patients (non-crossover group). At 36 months, the change in office systolic blood pressure was –26·4 mm Hg (SD 25·9) in the renal artery denervation group and –5·7 mm Hg (24·4) in the sham control group (adjusted treatment difference –22·1 mm Hg [95% CI –27·2 to –17·0]; p≤0·0001). The change in 24 h ambulatory systolic blood pressure at 36 months was –15·6 mm Hg (SD 20·8) in the renal artery denervation group and –0·3 mm Hg (15·1) in the sham control group (adjusted treatment difference –16·5 mm Hg [95% CI –20·5 to –12·5]; p≤0·0001). Without imputation, the renal artery denervation group spent a significantly longer time in therapeutic blood pressure range (ie, better blood pressure control) than patients in the sham control group (18% [SD 25·0] for the renal artery denervation group vs 9% [SD 18·8] for the sham control group; p≤0·0001) despite a similar medication burden, with consistent and significant results with imputation. Rates of adverse events were similar across treatment groups, with no evidence of late-emerging complications from renal artery denervation. The rate of the composite safety endpoint to 48 months, including all-cause death, new-onset end-stage renal disease, significant embolic event resulting in end-organ damage, vascular complication, renal artery re-intervention, and hypertensive emergency was 15% (54 of 352 patients) for the renal artery denervation group, 14% (13 of 96 patients) for the crossover group, and 14% (10 of 69 patients) for the non-crossover group. This final report of the SYMPLICITY HTN-3 trial adds to the totality of evidence supporting the safety of renal artery denervation to 36 months after the procedure. From 12 months to 36 months after the procedure, patients who were originally randomly assigned to receive renal artery denervation had larger reductions in blood pressure and better blood pressure control compared with patients who received sham control. Medtronic

In this trial, patients with type 2 diabetes had a lower incidence of major cardiovascular outcomes with a systolic blood-pressure target of less than 120 mm Hg than with a target of less than 140 mm Hg.

The prevalence of uncontrolled hypertension is high and increasing in low-income and middle-income countries. We tested the effectiveness of a multifaceted intervention for blood pressure control in rural China led by village doctors (community health workers on the front line of primary health care). In this open, cluster randomised trial (China Rural Hypertension Control Project), 326 villages that had a regular village doctor and participated in the China New Rural Cooperative Medical Scheme were randomly assigned (1:1) to either village doctor-led multifaceted intervention or enhanced usual care (control), with stratification by provinces, counties, and townships. We recruited individuals aged 40 years or older with an untreated blood pressure of 140/90 mm Hg or higher (≥130/80 mm Hg among those with a history of cardiovascular disease, diabetes, or chronic kidney disease) or a treated blood pressure of 130/80 mm Hg or higher. In the intervention group, trained village doctors initiated and titrated antihypertensive medications according to a standard protocol with supervision from primary care physicians. Village doctors also conducted health coaching on home blood pressure monitoring, lifestyle changes, and medication adherence. The primary outcome (reported here) was the proportion of patients with a blood pressure of less than 130/80 mm Hg at 18 months. The analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, NCT03527719, and is ongoing. Between May 8 and November 28, 2018, we enrolled 33 995 individuals from 163 intervention and 163 control villages. At 18 months, 8865 (57·0%) of 15 414 patients in the intervention group and 2895 (19·9%) of 14 500 patients in the control group had a blood pressure of less than 130/80 mm Hg, with a group difference of 37·0% (95% CI 34·9 to 39·1%; p<0·0001). Mean systolic blood pressure decreased by −26·3 mm Hg (95% CI −27·1 to −25·4) from baseline to 18 months in the intervention group and by −11·8 mm Hg (−12·6 to −11·0) in the control group, with a group difference of −14·5 mm Hg (95% CI −15·7 to −13·3 mm Hg; p<0·0001). Mean diastolic blood pressure decreased by −14·6 mm Hg (−15·1 to −14·2) from baseline to 18 months in the intervention group and by −7·5 mm Hg (−7·9 to −7·2) in the control group, with a group difference of −7·1 mm Hg (−7·7 to −6·5 mm Hg; p<0·0001). No treatment-related serious adverse events were reported in either group. Compared with enhanced usual care, village doctor-led intervention resulted in statistically significant improvements in blood pressure control among rural residents in China. This feasible, effective, and sustainable implementation strategy could be scaled up in rural China and other low-income and middle-income countries for hypertension control. Ministry of Science and Technology of China.