bluuebunny/crossref_metadata_2025_split huggingface dataset:
UNCOVERING ASSOCIATIONS BETWEEN BLOOD PRESSURE PHENOTYPES AND IMMUNE TRAITS IN TWINSUK
Authors: Christofidou Paraskevi , Menni Christina , Liechti Thomas , Roederer Mario , Spector Tim , Mangino Massimo 
Published: April 2021

Objective:
The primary aim of this work was to define the contribution of both the innate and adaptive immune system arms to blood pressure changes.

Design and method:
In order to define the inter-relationships between immune cell subtypes, blood pressure (BP) and susceptibility to hypertension (HT), we carried out association analyses between 23,394 immune phenotypes and blood pressure measures [systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse pressure (PP)] and HT.
After calculating the mean SBP and DBP values from two BP measurements, we adjusted for medication use by adding 15- and 10-mm Hg to SBP and DBP respectively for individuals reported to be on BP-lowering treatment. PP was calculated as SBP minus DBP according to medication adjusted traits. HT was defined as (i) SBP>=140 mm Hg, (ii) DBP>=90 mm Hg or taking BP-lowering medication.
We undertook a comprehensive and high-resolution deep immunophenotyping flow-cytometry approach, to examine immune traits in 502 female twins from TwinsUK. The platform used covered all major lymphocyte and myeloid subsets in peripheral blood. A linear/logistic mixed model regression analysis adjusted for family structure, age and BMI was used to examine the associations between immune traits and blood pressure phenotypes and HT status respectively.

Results:
We observed statistically significant associations (Bonferroni P-value < 1.71x10–4) between blood pressure phenotypes and immune cell subtypes. In particular, DBP showed 47 significant associations with distinct myeloid cell types of CD8 differentiation T cells. SBP showed 59 significant associations with both CD8 differentiation T cells and specific myeloid subpopulations such as monocytes. PP showed 4 significant associations with monocyte subpopulations. Analysis of HT revealed 7 associations with monocytes, CD8 T cells and dendritic cells.

Conclusions:
The results reported in this study provide preliminary evidence of an inter-relationship between blood pressure and human immune cell profile associations. We have shown for the first time that change in the proportions of immune cells correlates with blood pressure measurements.
EFFECTS OF FEBUXOSTAT ON CAROTID INTIMA-MEDIA THICKNESS IN ASYMPTOMATIC HYPERURICEMIA: A RANDOMIZED CLINICAL TRIAL (PRIZE)
Authors: Tanaka Atsushi , Taguchi Isao , Teragawa Hiroki , Ishizaka Nobukazu , Murohara Toyoaki , Node Koichi 
Published: April 2021

Objective:
Elevated levels of serum uric acid (SUA) increase the risk of gout and may be associated with the risk of cardiometabolic disorders and subsequent cardiovascular disease. Clinical evidence regarding the effects of xanthine oxidase (XO) inhibitors on atherosclerosis is lacking. The purpose of the study was to test whether treatment with febuxostat, a non-purine selective inhibitor of XO, delays carotid intima-media thickness (IMT) progression in patients with asymptomatic hyperuricemia.

Design and method:
This was an investigator-initiated, multicenter, randomized, controlled, open-label clinical trial undertaken at 48 Japanese sites. A total of 514 adults, who had both asymptomatic hyperuricemia with SUA >7.0 mg/dL and maximum IMT of the common carotid artery (CCA) 1.1 mm or greater at screening, were equally allocated to receive either dose-titrated febuxostat (10–60 mg daily) or non-pharmacological lifestyle modification for hyperuricemia as a control-arm. The primary endpoint was the percentage change from baseline in mean IMT of the CCA at 24 months. Key secondary outcomes included other carotid ultrasonographic parameters, SUA, and adverse events.

Results:
Compared with the control group, febuxostat had no significant effect on the primary endpoint (1.2% [95% CI, -0.6% to 3.0%] in the febuxostat group vs 1.4% [95% CI, -0.5% to 3.3%] in the control group; between-group difference [febuxostat-control], -0.2% [95% CI, -2.3% to 1.9%]; P = 0.83) and any other carotid ultrasonographic parameters. At 24 months, the between-group difference [febuxostat-control] in the SUA change from baseline was significant (-2.65 mg/dL [95% CI, -2.93 mg/dL to -2.37 mg/dL]; P < 0.001), and gout arthritis occurred only in the control group (4 patients [1.6%]). There were three deaths in the febuxostat group and seven in the control group during follow-up.

Conclusions:
In Japanese patients with asymptomatic hyperuricemia, 24 months of febuxostat treatment did not delay carotid atherosclerosis progression, compared with non-pharmacological care. These findings do not support the use of febuxostat for delaying carotid atherosclerosis in this population. However, febuxostat treatment was tolerable and did not increase the incidence of cardiovascular and all-cause mortality.
OPTIMAL DRUGS FOR MEDICATION REDUCTION: SECONDARY ANALYSIS OF THE OPTIMISE MEDICATION REDUCTION TRIAL
Authors: Sheppard James , Lown Mark , Burt Jenni , Temple Eleanor , Ford Gary , Hobbs Richard , Little Paul , Mant Jonathan , Payne Rupert , McManus Richard 
Published: April 2021

Objective:
Deprescribing of antihypertensive medications is recommended in some elderly patients with polypharmacy and multi-morbidity. The OPTiMISE trial demonstrated that antihypertensive medication reduction can be achieved in two thirds of patients without changes in systolic blood pressure (SBP) control or serious adverse events at 12-week follow-up. The present analyses aimed to examine whether specific drug types were associated with more successful medication reduction in the intervention arm of the trial.

Design and method:
A total of 282 participants, aged at least 80 years with SBP < 150 mmHg and receiving 2 or more antihypertensive medications were randomised to medication reduction and included in the present analyses. Successful medication reduction was defined by the proportion of participants maintaining reduced medications. Secondary outcomes examined the association between drug class and change in SBP and adverse events. Multivariate regression analyses were conducted to examine associations adjusted for age, sex, systolic blood pressure, cardiovascular disease, multimorbidity, polypharmacy and frailty.

Results:
Participants included in the analysis were aged 84.6 years, with controlled hypertension (mean SBP 129.4 mmHg), polypharmacy (mean 5.4 medications) and multimorbidity (98.8% participants had 2 or more morbidities). More participants withdrawing ACE inhibitors (79.4%) and beta-blockers (80.6%) were able to maintain medication reduction more than any other drug throughout 12-week follow-up. Half (50.0%) of participants who had these medications removed experienced no increase in SBP at follow-up. In multivariate analyses, calcium channel blockers were less likely to remain withdrawn at follow-up (OR 0.31, 95% CI 0.12 to 0.86), whilst withdrawal of beta-blockers was associated with a significant reduction in SBP (-9.5 mmHg, 95% CI -16.8 to -2.1 mmHg). There was no association between removal of specific drug classes and subsequent adverse events.

Conclusions:
In the OPTiMISE medication reduction trial, beta-blockers were more likely to be successfully reduced and have little impact of follow-up blood pressure than any other antihypertensive drug class. When considering reducing antihypertensive medications due to polypharmacy, beta-blockers should be targeted as a first-line therapy for deprescribing, followed by ACE inhibitors in older patients with controlled hypertension.
STRATIFIED EFFECTS OF BLOOD PRESSURE-LOWERING TREATMENT ON LONG-TERM BLOOD PRESSURE: A META-ANALYSIS OF INDIVIDUAL-LEVEL DATA OF 334,219 PARTICIPANTS FROM 50 RANDOMIZED TRIALS
Authors: Canoy Dexter , Copland Emma , Ramakrishnan Rema , Pinho-Gomes Ana -Catarina , Nazarzadeh Milad , Bidel Zeinab , Salimi-Khorshidi Gholamreza , Woodward Mark , Davis Barry R. , Pepine Carl J. , Chalmers John , Teo Koon , Rahimi Kazem 
Published: April 2021

Objective:
Evidence on the magnitude of blood pressure (BP)-lowering treatment effects in large-scale randomised clinical trials is limited but is pertinent for explaining treatment effects on cardiovascular outcomes and for policy planning. We determined the effects of BP-lowering treatment on long-term BP overall and across important patient subgroups defined by their characteristics.

Design and method:
We conducted a one-stage individual patient-level data meta-analysis (N = 50 trials). We analysed data separately by trial design, and fitted mixed models (with fixed treatment effects, fixed time effect, random intercepts at trial and participant level, and a random slope for time at participant level). Models were adjusted for age, sex and baseline BP (except when used as stratification factor) and compared using likelihood ratio test and Akaike information criterion.

Results:
The analysis included 334,219 (42% women) participants with mean age = 65 years, and among whom 18% were current smokers, 47% had CVD, 29% had diabetes, and 73% were previously on BP-lowering medication. Over 4 years of follow-up, participants had an average of 8 BP measurements. For BP-lowering intensity trials (N = 8), mean differences (95% confidence interval) in systolic BP (SBP) and diastolic BP (DBP) between comparison arms were 8.2 (8.0 to 8.4) mmHg and 3.7 (3.6 to 3.9) mmHg, respectively, for placebo-controlled trials (N = 21) the SBP and DBP differences were 4.2 (4.0 to 4.3) mmHg and DBP 1.9 (1.9 to 2.0) mmHg, respectively, and for drug comparison trials (N = 28) the SBP and DBP differences were 1.3 (1.2 to 1.3) mmHg and 0.5 (0.5 to 0.5) mmHg, respectively. The reduction in BP differed by follow-up duration and patient characteristics, particularly for placebo-controlled and BP-lowering intensity trials, which showed substantial heterogeneity in BP reductions according to baseline BP, age, sex, prior CVD, diabetes and non-randomised anti-hypertensive use.

Conclusions:
Pharmacologic agents are effective in reducing long-term BP across individuals with different characteristics. In large-scale trials, the magnitude of BP reduction varied by several patient characteristics, which could have implications on interpretation of any differential effects of BP treatment on major clinical outcomes.
OPTIMAL THRESHOLDS FOR AMBULATORY BLOOD PRESSURE IN PATIENTS WITH HIGH CARDIOVASCULAR RISK
Authors: Jaehyung Ha , Chanjoo Lee , Hyoeun Kim , Kyeong-Hyeon Chun , Jaewon Oh , Sang-Hak Lee , Seok-Min Kang , Sungha Park 
Published: April 2021

Objective:
Recent 2017 American College of Cardiology/American Heart Association hypertension guideline suggested new ambulatory blood pressure (ABP) thresholds, however there are arguments whether it is optimal for defining hypertension. The objective of this study was to find optimal ABP thresholds for outcomes especially in patients with high cardiovascular risk.

Design and method:
From the Cardiovascular and Metabolic Disease Etiology Research Center – High Risk Cohort (CMERC-HI), 2026 patients who had 24-hour ABP monitoring data were selected. Baseline 24-hour ABP, daytime ABP, nighttime ABP, morning ABP threshold were determined separately using Cox proportional hazard model with propensity scores adjustment. The composite of cardiovascular disease (CVD) outcomes (hospitalization with MI, stroke, or heart failure) and all-cause mortality were primary end-points of this study.

Results:
A total of 2026(median age, 60 years, 52.6% male) subjects were analyzed in this study. Median follow-up was 3.4 years. There were 54 CVD outcomes and all-cause mortality (8.1 per 1000 person-years). Compared to 24-hour ABP <135/85 mmHg, 24-hour ABP more than 135/85 mmHg was associated with significantly poor outcomes (HR 1.49, 95% CI, 1.02–2.17). However, 24-hour ABP more than 130/80 mmHg and 24-hour ABP more than 125/75 were not associated with significantly higher risk. For daytime ABP, the threshold of 140/90 mmHg was significantly related to higher risk of CVD outcomes or death, (HR 1.78, 95% CI, 1.04–3.05) rather than ABP 135/85 mmHg or 130/80 mmHg. For nighttime ABP, no cut-off level other than 125/75 mmHg (HR 1.58, 95% CI, 1.08–2.32) was statistically meaningful. There was no adequate threshold for morning ABP in this analysis.

Conclusions:
In patients with high risk for CVD, 135/85mmHg for 24hr-ABP, 140/90 mmHg for daytime ABP, 125/75 mmHg for nighttime ABP seemed to be the threshold associated with increased outcomes. The BP threshold suggested by the ACC/AHA guideline was not significantly associated with increased outcomes.
GENETIC BACKGROUND DOMINATES FIBROTIC AORTIC REMODELING DURING ANGIOTENSIN-INDUCED HYPERTENSION IN MICE
Authors: Spronck Bart , Caulk Alexander W. , Ramachandra Abhay B. , Murtada Sae -Il , Rojas Alexia , He Chang -Shun , Bersi Matthew R. , Tellides George , Humphrey Jay D. 
Published: April 2021

Objective:
Many induced genetic mutations affect aortic structure and function in mice, but less is known about the influence of background strain. This study quantifies and compares the aortic phenotype in angiotensin II (AngII)-induced hypertension across different strains of wild-type mice.

Design and method:
Adult C57BL/6J and 129SvEv mice were studied before and after induction of hypertension via subcutaneous infusion of AngII (1000 ng/kg/min) for two weeks, which elevated blood pressure similarly in both strains (+34% vs. +32%, systolic). Excised descending thoracic aortas were subjected to a series of isobaric vasocontraction and vasorelaxation tests as well as novel biaxial stiffness testing. Immuno-histological studies quantified medial and adventitial composition as well as CD45+ cellular infiltration.

Results:
Baseline aortic geometry and biomechanical properties were similar across strains, consistent with the existence of general homeostatic mechanical targets. Nevertheless, aortic remodeling due to AngII-induced hypertension differed dramatically between strains, with gross over-adaptive remodeling (exuberant thickening of the media and adventitia) in C57BL/6J (+89% thickness increase) but under-adaptive remodeling in 129SvEv mice (+12% thickness increase). Importantly, vasoconstrictive strength was lower in C57BL/6J than 129SvEv mice, both before (-4% vs. -11% contractile change in outer diameter (δOD), p = 0.020; -8 vs. -24% contractile change in circumferential stress (δσ), p = 0.023) and after (-10% vs. -22% contractile δOD, p < 0.001; -24 vs. -46% contractile δσ, p < 0.001) hypertension. CD45+ cell content was markedly higher in C57BL/6J than 129SvEv mice following hypertension (p < 0.001). When considering individual vessels, wall thickness correlated with both CD45+ content (p = 0.034) and total contractility (p = 0.001), with contractility the strongest predictor statistically. Finally, layer-specific biomechanical analyses revealed increased adventitial load bearing in the hypertensive 129SvEv aorta under passive conditions, which, however, it is able to normalize by its increased contractility.

Conclusions:
Genetic modifiers play key roles in the different hypertensive aortic remodeling between C57BL/6J and 129SvEv mice (Figure) as well as mixed C57BL/6;129SvEv mice. The lower fibrotic response in 129SvEv mice results from their lower inflammatory state but also their greater aortic vasoresponsiveness to AngII, which lowers the wall-stress associated mechano-stimulus for remodeling. Remodeling in mixed-background mice was dominated by the 129SvEv strain.
ARTERIAL STIFFNESS AND ORTHOSTATIC BLOOD PRESSURE CHANGES IN HYPERTENSIVE ADULTS – RESULTS FROM SEPHAR III SURVEY
Authors: Fronea Oana Florentina Gheorghe , Darabont Roxana , Pop Calin , Dorobantu Maria 
Published: April 2021

Objective:
To evaluate the relationship between orthostatic hypotension (OH) and arterial stiffness in controlled and uncontrolled hypertensive adults

Design and method:
Eight hundred eighty-nine hypertensive subjects identified in SEPHAR III national-representative survey (aged 18 to 80 years; mean age 48.5 ± 17.5 years, 52.5%females, 81,3% treated, 30,8% controlled) were studied. BP in both sitting and at 1 and 3 minutes after standing up was measured. Arterial stiffness was assessed by PWVao measured by a sphygmomanometric method (Arteriograph). Orthostatic hypotension (OH) was defined by SBP decrease of at least 20mmHg and/or DBP decrease of at least 10mmHg at 3 minutes after standing.

Results:
Orthostatic Hypotension was identified in 161 subjects, representing 19% of the sample., with significantly higher prevalence among uncontrolled hypertensive subjects (21,3% vs. 10.9%, p = 0,001)
In uncontrolled hypertensive subjects, the orthostatic alterations in systolic, but not in diastolic blood pressure (DBP), were inversely related to PWV, independently from age, gender, mean BP, and diabetes mellitus.
In uncontrolled hypertensive subjects the greater the aortic stiffness the larger was the systolic blood pressure (SBP) decrease after assuming orthostatic position. On the contrary, no such association was found between PWV and orthostatic changes of BP in controlled hypertensive subjects.

Conclusions:
Our results suggest the presence of a pathophysiological association between arterial stiffening and BP postural changes in hypertensive adults. Antihypertensive drug treatment, as well as other factors that have not been evaluated in the present study, might have modulated this association.
DIFFERENCE BETWEEN CHRONOLOGICAL AND VASCULAR AGE AS A PREDICTOR FOR CARDIOVASCULAR EVENTS - IDENTIFICATION OF PATIENTS WITH SUPERNORMAL VASCULAR AGING (SUPERNOVA)
Authors: Bruno Rosa Maria , Nilsson Peter , Engsrtöm Gunnar , Wadström Benjamin , Empana Jean -Philippe , Boutouyrie Pierre , Laurent Stéphane 
Published: April 2021

Objective:
Pulse wave velocity (PWV) is an established marker of early vascular aging (EVA), but may also help identifying individuals with supernormal vascular aging (SUPERNOVA). Aim of this study is to test the hypothesis that individuals with the largest difference between chronological and vascular age (Delta-age), calculated from classical CV risk factors and PWV, show the lowest rate of CV events, and may thus be defined SUPERNOVA.

Design and method:
Vascular age was calculated according to the best fitting model for chronological age prediction, in the cross-sectional Reference Values for Arterial stiffness Collaboration Database (n = 11,406), for different age categories. The risk of fatal and non-fatal CV events associated with Delta-age was investigated in the longitudinal Malmö Diet and Cancer Study cohort (n = 2642). Delta-age deciles were used to define EVA (<3.0 years), normal vascular ageing (VA, 3.0 to 8.8 years) and SUPERNOVA (>8.8 years).

Results:
In the Reference Values Database, the most significant predictor of vascular age (full model r2 = 0.598) was PWV. In the Malmö Diet and Cancer Study Cohort (6.6-year follow-up, 286 events). Delta-age was significantly and inversely associated with CV events. Compared to normal VA, SUPERNOVA had lower risk [HR 0.55 (95%CI 0.36–0.82)], whereas EVA had higher risk [HR 2.88 (95%CI 1.88–4.40)]. There was no significant association with all-cause mortality.

Conclusions:
PWV proved to be useful to identify SUPERNOVA individuals. Further characterization of this extreme phenotype may help discovering novel protective molecular pathways and providing preventive strategies for successful vascular aging.
CAROTID-TO-FEMORAL PULSE TRANSIT TIME VARIABILITY PREDICTS ALL-CAUSE AND CARDIOVASCULAR MORTALITY IN CHINESE AND SWEDISH ELDERLY
Authors: An Dewei , Muhammad Iram Faqir , Guo Qian -Hui , Borné Yan , Sheng Chang -Sheng , Persson Margaretha , Cheng Yi -Bang , Wang Ji -Guang , Engström Gunnar , Li Yan , Nilsson Peter 
Published: April 2021

Objective:
Acquisition of pulses at carotid and femoral arteries allows measurement of carotid-femoral pulse wave velocity (cf-PWV) via determination of pulse transit time (PTT) and pulse travelled distance. PWV predicts adverse outcome and contributes to risk stratification. However, little is known about the PTT variability during the cf-PWV measurement and its predictive value.

Design and method:
Community-based prospective cohorts of elderly population from Shanghai, China and Malmö, Sweden were included in the study. The cf-PWV, cf-PTT and its coefficient of variation (CV) were measured with the Sphygmocor device. Vital status in both cohorts and cause of death in the Malmö subjects were ascertained. Cox proportional hazard model and Fine-Gray competing risk model were applied for analysis.

Results:
Of the 1249 (median age, 75.6 years; 42.5% men) and 2999 (72.4 years; 39.6% men) participants from Shanghai and Malmö who were followed up for a median of 8.9 and 6.6 years, respectively, 292 (23.3%) and 388 (12.9%) died, respectively. The cf-PWV (median: 9.4 vs. 8.7 m/s in Shanghai and 11.2 vs. 9.9 m/s in Malmö) and CV of cf-PTT (median: 8.6 vs. 7.4 % in Shanghai and 9.0 vs. 7.9 % in Malmö) were significantly higher in the deceased people compared to those survived. Age, body mass index, heart rate, mean blood pressure and pulse pressure were determinants (P < 0.05) of the CV of PTT in both cohorts. Each 1-standard deviation increase in the log-transformed CV of cf-PTT was associated with a 14% (95% CI, 1–28%) increased risk of all-cause mortality in Shanghai subjects and 25% (13–37%) and 59% (34–89%) increased risk of all-cause and cardiovascular mortality in Malmö subjects. Adding the CV of cf-PTT to the models including cf-PWV had significant net reclassification improvement (0.202 [0.062–0.321]; P = 0.007) and integrated discrimination improvement (0.013[0.001–0.039]; P = 0.02) for cardiovascular mortality in Malmö subjects.

Conclusions:
The variability of cf-PTT during the cf-PWV measurement was predictive of mortality and improved risk prediction in the elderly.
EVALUATION OF CENTRAL HEMODYNAMICS USING THE RADIAL ARTERIAL PULSE WAVE IN CHILDREN AND YOUNG ADULTS
Authors: Murakami Tomoaki , Shiraishi Masahiro , Takeda Atsuhito 
Published: April 2021

Objective:
Evaluation of central hemodynamics is useful in prevention and treatment of cardiovascular diseases. In this study, we examined the accuracy of non-invasively measured central hemodynamics in children and young adults.

Design and method:
This study enrolled 19 patients who had undergone a cardiac catheterization below 28 years old (9.7 ± 7.3 years). Ascending aortic blood pressure was measured recorded using a pressure sensor-mounted catheter (model SPC-454D, Millar Instrument, Inc., Houston, Texas). Radial artery pulse waves were simultaneously measured non-invasively by tonometry (HEM-9000AI, Omron Healthcare Co., Ltd., Kyoto, Japan). We analyzed the degree of coincidence between ascending aortic systolic blood pressure (aSBP) and estimated central systolic blood pressure by tonometry (estCBP) using 36 simultaneous recording of aSBP and estCBP. We also analyzed the relationship between aortic augmentation index (aAI) and radial augmentation index (rAI).

Results:
The aSBP was 95.5 ± 13.1 mmHg and estCBP was 88.5 ± 19.9mmHg. There was a significant relationship between aBP and estCBP (aSBP = 0.78 (estCBP) + 22.7, r = 0.82, p < 0.01). The mean difference of the aSBP minus eCBP was 2.6 ± 8.0 mmHg by Bland-Altman analysis. The rAI was 64.0 ± 15.1% and aAI was 14.9 ± 10.0%. There was a significant correlation between two parameters (r = 0.40, p = 0.015).

Conclusions:
The estimation of central hemodynamics by the radial artery tonometry is useful for children and young adults.