bluuebunny/crossref_metadata_2025_split huggingface dataset:
BLOOD PRESSURE LOWERING EFFECTS AND SAFETY OF ESEXERENONE, NEWLY AVAILABLE MINERALOCORTICOID RECEPTOR BLOCKER
Authors: Satoh Fumitoshi , Morimoto Ryo , Tezuka Yuta , Omata Kei , Yamanami Hiroaki , Ono Yoshikiyo , Ito Sadayoshi 
Published: April 2021

Objective:
Esaxerenone (CS-3150) is a novel, highly potent, selective and long acting non-steroidal mineralocorticoid receptor (MR) blocker with MR blocking action of IC50 3.7 nM, other steroid hormone receptors blocking action of IC50 >5000 nM and half life loss of 18.6 hours. The authors aimed to investigate blood pressure (BP)-lowering ability and safety of esaxerenone in resistant hypertensive patients by add-on or by replacement from spironolactone or eplerenone.

Design and method:
This study was designed as a prospective observational study in 230 patients, approved by the local ethical committee and followed for 12 weeks. In add-on group, 52 resistant hypertensive patients, whose office BP was > 130/80 (<75 years old) or 140/90 (>75 years old) treated with at least three hypertensive agents (CCBs, RAS inhibitors and diuretics) according to the Japanese Society of Hypertension Guidelines for the Management of Hypertension (JSH 2019), were treated by the add-on use of esaxerenone. In replacement group, 208 resistant hypertensive patients, whose BP was controlled by at least 4 antihypertensive drugs including spironolactone or eplerenone, were medicated with esaxerenone by replacement from spironolactone or eplerenone.

Results:
In add-on group, both systolic and diastolic BP were significantly lowered from 139 ± 16 / 82 ± 14 mmHg (means ± SD) to 129 ± 16 / 79 ± 12 mmHg (p < 0.0001 and p = 0.0185, respectively) with mean esaxerenone dose of 1.44 mg. In replacement group, systolic BP was significantly lowered from 126 ± 16 mmHg (means ± SD) to 120 ± 14 mmHg (p < 0.0001), but diastolic BP was not, with mean esaxerenone dose of 1.58 mg once a day, which was changed from mean spironolactone and eplerenone doses of 34 and 58 mg, respectively. In add-on group, serum potassium concentration was significantly increased from 4.18 ± 0.46 to 4.40 ± 0.58 mmol/L and eGFR was decreased from 74.2 ± 23.9 to 66.9 ± 24.0, but those in replacement group were not significantly changed.

Conclusions:
This study suggested that esaxerenone has more potent BP lowering ability than spironolactone or eplerenone especially in systolic BP and has the equivalent safety.
RECEPTOR INTERACTING MOLECULE ATRAP AS MODULATOR OF RENAL SODIUM HANDLING AND PATHOLOGICAL BLOOD PRESSURE RESPONSE
Authors: Tamura Kouichi , Yamaji Takahiro , Kinguchi Sho , Kobayashi Ryu , Azushima Kengo , Uneda Kazushi , Haruhara Kotaro , Kanaoka Tomohiko , Urate Shingo , Abe Eriko , Tanaka Shohei , Ishii Takeo , Kumagai Tomohiko , Yamashita Akio , Wakui Hiromichi 
Published: April 2021

Objective:
Pathological activation of renal angiotensin II (Ang II) type 1 receptor (AT1R) signaling exerts stimulates renal tubular Na+ transporters including epithelial Na+ channel to increase renal sodium reabsorption.

Design and method:
In the course of an investigational search for a means to functionally and selectively modulate AT1R signaling for that purpose, a molecule directly interacting with the carboxyl-terminal cytoplasmic domain of AT1R was identified by employing yeast two-hybrid screening of a mouse kidney cDNA library and named AT1R-associated protein (ATRAP).

Results:
We showed that ATRAP promotes constitutive AT1R internalization so as to inhibit pathological AT1R activation in response to certain stimuli. In the kidney, ATRAP is abundantly distributed in epithelial cells along the renal tubules. The results employing genetic engineered mice with modified ATRAP expression showed that ATRAP plays a key role in the regulation of renal sodium handling and the modulation of blood pressure in response to pathological stimuli such as chronic Ang II infusion dietary high salt loading and 5/6 nephrectomy.

Conclusions:
Accumulating findings concerning functional and pathological roles of the novel receptor-interacting molecule ATRAP suggest that ATRAP would be a target of interest for hypertension in the cardiovascular and renal continuum.
ASSOCIATION BETWEEN THE DIFFERENCE OF BILATERAL BRACHIAL-ANKLE PULSE WAVE AND CARDIOVASCULAR EVENTS, ALL-CAUSE MORTALITY
Authors: Zheng Mengyi , Wu Shouling 
Published: April 2021

Objective:
Aims: To assess whether an elevated bilateral pulse wave velocity difference (BPWVD) is associated with a higher risk of cardiovascular disease (CVD) and all-cause mortality.
Methods and

Design and method:
From the community-based longitudinal Kailuan Study, we included 38,512 participants (mean age:48.9 ± 12.8 years) who underwent measurements of the brachial-ankle pulse wave velocity (baPWV) from 2010 to 2017, and who were followed to 2018 for CVD outcome and to 2019 for the assessment of all-cause mortality. During a mean follow-up of 4.25 ± 2.39 years for assessment of CVD and 5.23 ± 2.39 years of all-cause mortality, 815 CVD cases (cerebral infarction, n = 566; intracerebral hemorrhage, n = 70; myocardial infarction, n = 179) and 952 mortalities were identified. The mean BPWVD was 63.0 cm/s (median:43 cm/s; inter-quartile range:19, 80 cm/s), and 9,708 (25.2%) participants were categorized as the high BPWVD group with a BPWVD in the highest quartile (?80 cm/s). In the multivariable Cox proportional hazard model, compared with the normal BPWVD group, the high BPWVD group had a significantly higher risk of myocardial infarction and all-cause mortality, with adjusted hazard ratios (HRs) (95% confidence interval (CI)) of 1.43 (95%CI: 1.04–1.96) and 1.18 (95%CI: 1.03–1.35), respectively. A higher BPWVD by one standard deviation was associated with HRs of 1.06 (95% CI: 1.02–1.10) for incident CVD, 1.10 (95% CI: 1.02–1.17) for incident myocardial infarction and of 1.07 (95% CI: 1.04–1.10) for all-cause mortality.

Conclusion:
Higher BPWVD was positively associated with the risks of CVD and all-cause mortality. Our findings emphasize the importance of assessing BPWVD to identify high-risk individuals for CVD and mortality.
VASCULAR AGING INDEPENDENTLY PREDICTS ALL-CAUSE MORTALITY IN THE HEINZ NIXDORF RECALL STUDY
Authors: Weber Thomas , Wassertheurer Siegfried , Hametner Bernhard , Mayer Christopher , Moebus Susanne , Schramm Sara , Roggenbuck Ulla , Lehmann Nils , Joeckel Karl -Heinz , Erbel Raimund 
Published: April 2021

Objective:
Vascular aging is an attractive concept for simplified risk stratification. Longitudinal data regarding its predictive value, additive to traditional and new risk factors, are sparse.

Design and method:
We recently established population-based reference values for healthy (HVA), normal (NVA) and early (EVA) vascular aging in the Heinz Nixdorf Recall (HNR) study. HVA was the lowest, and EVA the highest age- and sex-specific decile of estimated aortic pulse wave velocity, derived from radial waveforms with a validated regression formula. The prognostic value of vascular aging was tested in HNR study participants without overt cardiovascular disease at baseline, using Kaplan Meier curves and Cox Regression models. The latter included age, sex, diastolic blood pressure, cholesterol, diabetes, smoking status and coronary calcium (Agatston score) as covariates.

Results:
We included 1810 participants (980 women), mean age was 68.1 years (range 55–85), mean blood pressure 129/76 mm Hg. 64.6% were hypertensives, 17.0% diabetics, 12.2% smokers. During a mean follow up of 4.7 years, 67 participants died. Mortality was 1.22% in 164 HVA participants, 3.59% in 1392 NVA participants, and 5.91% in 254 EVA participants (p = 0.038, log rank test) – Figure. In Cox regression analysis, vascular aging (HR for HVA: 0.18, CI 0.04–0.73, and HR for NVA: 0.48, CI 0.27–0.88; both compared to EVA) as well as age (directly related) and diastolic blood pressure (inversely related) were independently associated with all-cause mortality.

Conclusions:
Vascular aging, determined from estimated aortic pulse wave velocity, predicts all-cause mortality in a middle-aged and elderly population, independent from classic risk factors, and coronary calcium score.
THE EFFECTS OF ITI-214 (A NEW PHOSPHODIESTERASE 1 INHIBITOR) ON VASCULAR AGEING FEATURES ASSOCIATED TO DNA REPAIR RESPONSE IN MICE
Authors: Golshiri Keivan , Ataei Ehsan , De Vries Rene’ , Van Veghel Richard , Snyder Gretchen L. , Zhang Lei , Li Peng , Davis Robert E. , Danser A.H. Jan , Roks Anton J.M. 
Published: April 2021

Objective:
DNA damage and repair responses have been linked to accelerated vascular aging. Accordingly, mice with a genetic deletion of ERCC1 (Ercc1d/- mice), a DNA repair protein, display a rapid onset of vascular aging. A hallmark hereof is disturbed NO-cGMP signalling, in which an increase of the cyclic nucleotide-metabolizing enzyme phosphodiesterase 1 (PDE1) is implicated. We hypothesized that specific PDE1 inhibition has beneficial effects in the aged vasculature. To test this, we evaluated the effects of chronic and acute PDE1 inhibition with ITI-214 in Ercc1d/- mice and WT littermates.

Design and method:
ITI-214 (treated), or no drug (control), was given in drinking water from the age of 6 to 14 weeks. Blood pressure (BP) and in vivo vasodilator responses (hindleg reactive hyperemia:RH) were measured in week 12 and 13. At 14 weeks aortic tissue was obtained for ex vivo wire myograph studies to analyse endothelium-dependent and endothelium-independent relaxations to acetylcholine (Ach) and nitric oxide donor (sodium nitroprusside: SNP) respectively.

Results:
There were significant reductions in systolic (93.39 ± 3.406 vs. 111.7 ± 5.238 mmHg, P = 0.009) and diastolic (64.47 ± 2.7 vs. 76.43 ± 4.699 mmHg, P = 0.038) BP in treated Ercc1d/- vs. controls. RH was 50% lower in control Ercc1d/- vs. WT (P = 0.025). ITI-214 treatment did not improve RH. In contrast, ITI-214 enhanced the aortic maximal Ach response from 70.24 ± 3.24 to 76.96 ± 4.76% (P = 0.002) and the SNP response from 64.83 ± 6.10 to 85.24 ± 7.58% (P = 0.0001) in WT but not in Ercc1d/-. In contrast to chronic treatment, acute administration of ITI-214 in organ baths enhanced the SNP response in both control WT (from 64.83 ± 6.10 to 79.32 ± 5.63%, P = 0.003) and control Ercc1d/- mice (from 45.61 ± 11.6 to 75.45 ± 3.61%, P = 0.0001).

Conclusions:
The acute effect of ITI-214 confirms the role of PDE1 in mediating decreased NO-cGMP signalling caused by defective DNA repair. Therefore, PDE1 inhibition is a strategy to acutely improve vasodilation in the aged vasculature.
DNA REPAIR DEFECT IN SMOOTH MUSCLE CELL REPRODUCES FEATURES OF AGE-RELATED VASCULAR DISEASE IN MICE
Authors: Ataabadi Ehsan Ataei , Golshiri Keivan , De Vries René , Snyder Gretchen L. , Zhang Lei , Li Peng , Davis Robert E. , Jan Danser A.H. , Roks Anton J.M. 
Published: April 2021

Objective:
DNA damage and repair responses have been implicated in age-related vascular disease. Evidence in mice shows that deletion of the Ercc1 gene, encoding an endonuclease that participates in several DNA repair systems, leads to features of accelerated ageing. It is not known from which cell type the vascular aging effect of Ercc1 deletion originates. A possibility is local DNA damage in vascular smooth muscle cells (VSMC). We determined features of vascular aging in a mouse model with specific Ercc1 deletion in smooth muscle cells (SMC-KO).

Design and method:
12 SMC-KO and 13 Wild-type (WT) littermates were generated using alpha SM22-Cre driven cre-lox deletion of Ercc1. Blood pressure (BP) and in vivo vasodilation (reactive hyperemia: RH) were measured at the age of 22 and 23 weeks respectively. Mice were sacrificed at 24 weeks. Thoracic aorta and iliac artery endothelium-dependent (ED) and –independent (EI) relaxation were assessed (wire myograph).

Results:
There was no significant difference in BP between WT and SMC-KO. RH was decreased in SMC-KO vs. WT by 73% (P = 0.008). In SMC-KO mice maximal relaxation in iliac arteries to acetylcholine (ED) and sodium nitroprusside donor (EI) were decreased as compared to WT (ED: 48.04 ± 6.80 vs. 86.16 ± 3.68, P = 0.001; EI: 79.84 ± 4.04 vs. 93.78 ± 2.13, P = 0.022). In aorta similar observations were made (ED: 17.11 ± 2.29 vs. 73.42 ± 4.29, P = 0.0001; EI 55.87 ± 4.77 vs. 69.01 ± 5.17, p = 0.007). When added in the organ bath ITI-214 acutely increased aortic EI relaxation both in WT (from 69.01 ± 5.17 to 80.53 ± 2.05, P = 0.006) and SMC-KO (from 55.87 ± 4.77 to 67.17 ± 3.70, P = 0.084).

Conclusions:
Local DNA damage in SMC causes a decrease of vasodilator responses. This effect is blood pressure-independent. Given that responses to sodium nitroprusside, a nitric oxide (NO) donor, and PDE1, a cGMP-metabolising enzyme, were both involved, most probably a decline of NO-cGMP signalling is involved.
MACHINE LEARNING CLUSTERING FOR BLOOD PRESSURE VARIABILITY: VALIDATION FROM THE SPRINT TO THE HONG KONG COMMUNITY COHORT
Authors: Tsoi Kelvin , Chan Nicholas , Yiu Karen , Poon Simon , Ho Kendall , Lin Bryant 
Published: April 2021

Objective:
Visit-to-visit BPV is associated with risks of cardiovascular diseases. Our aim is to investigate the classification methods of patients with varying levels of BPV using different machine learning algorithms.

Design and method:
Two sets of visit-to-visit blood pressure (BP) readings were extracted from (i) SPRINT in the United States and (ii) BP cohort in Hong Kong (HK). BPV were defined as the mean absolute residuals of regression trends on BP over time. Patients were clustered into low, medium and high levels of BPV with the traditional quantile clustering and five machine learning algorithms, including K-means clustering, Partitioning Around Medoids (PAM), Spectral clustering, Ward's method and Expectation Maximization. Clustering methods were assessed by the Stability Index, and similarities were assessed by the Davies-Bouldin Index (DBI) and the Silhouette Index. Regression models were fitted to compare the risk of stroke.

Results:
Results: A total of 8,133 participants were included from SPRINT with the mean BP measurement 14.7 times in 3.28 years of follow-up, and1,094 participants were recruited from HK cohort with the mean BP measurement 165.4 times in 1.37 years. Quantile clustering assigned one-third participants as the high level of BPV, but machine learning methods only assigned 10 to 27%. Quantile clustering is the most stable method (Stability Index: 0.982 in the SPRINT and 0.948 in the HK cohort) but shown to have certain levels of cluster similarities (DBI: 0.752 and 0.764, respectively) (Table 1). Across the machine learning algorithms, K-means clustering is the most stable method (Stability Index: 0.975 and 0.911, respectively) with lowest similarities on cluster classification (DBI: 0.653 and 0.680, respectively). Patients with high level of BPV under the machine learning models showed stronger association with stroke.

Conclusions:
Among the machine learning algorithms, K-means clustering shows the most stable and reliable results. One-seventh of the population with high level of BPV had elevated risk of stroke compared to conventional BPV classification. Machine learning can be potentially used in the electronic health system for better patient management.
MACHINE LEARNING BASED MODELS FOR PREDICTING WHITE-COAT AND MASKED PATTERNS OF BLOOD PRESSURE
Authors: Lip Stefanie , Mccallum Linsay , Reddy Sandeep , Chandrasekaran Nataraj , Tule Sanjana , Bhaskar Ravi Kiran , Padmanabhan Sandosh 
Published: April 2021

Objective:
Blood pressure (BP) is inherently variable. White-coat (WC) and masked hypertension are manifestations of this variability making office BP (OBP) unreliable with direct implications on diagnosis and management. Whilst the causes for this phenomenon are not fully known, predicting whether an individual's BP has WC or masked pattern will improve efficiencies in overall BP management. In this study, we used machine learning (ML) methods which are powerful in finding generalisable predictive patterns to develop models for accurate prediction of different BP patterns.

Design and method:
Data from patients referred from primary care to the specialist Glasgow BP clinic, all of whom underwent ambulatory blood pressure monitoring (ABPM) were analysed. The independent variables included a range of conventional clinical parameters included in the referral letter along with OBP. Missing data were imputed using K nearest neighbours, an ML algorithm that approximates a point value based on the nearest available point values. Following this, four ML algorithms (support vector machine, decision tree, random forest (RF) and extreme gradient boosting (XGBoost)) were applied to the dataset, split into 70% training and 30% validation subsets. Performance of models was reported using area under the curve, accuracy, precision (fraction of relevant instances among the retrieved instances) and recall (fraction of the total amount of relevant instances that were actually retrieved) measures.

Results:
There were 926 patients – average age 51 ± 16 years, 43%-female, 49% were new presentation for investigation of hypertension, 38% were not on any BP lowering therapy, 1.1% had type 2 diabetes and 5.2% had eGFR < 60. The proportion of different BP patterns were – Normal BP:8.1%, Normal BP-masked:3.7%, Normal BP-whitecoat: 30.7%, Hypertension-whitecoat:23.3% and Hypertension:34%. Of the four predictor models, the highest classification accuracies were obtained for the XGBoost algorithm (accuracy:85%, precision:85%) followed by the RF classifier (accuracy:84%, precision:84%). Figure-1 demonstrates the multiclass AUC and leading predictors using the XGBoost model.

Conclusions:
ML models are able to predict WC and masked patterns in hypertensive patients and those suspected of having hypertension with relatively high accuracy and this warrants validation in larger cohorts.
DIPPING PATTERN AND SHORT-TERM BLOOD PRESSURE VARIABILITY ARE STRONGER PREDICTORS OF CARDIOVASCULAR EVENTS THAN AVERAGE 24-HOUR BLOOD PRESSURE IN HYPERTENSION OF THE YOUNG
Authors: Palatini Paolo , Reboldi Paolo , Saladini Francesca , Angeli Fabio , Mos Lucio , Fania Claudio , Mazzer Adriano , Vriz Olga , Verdecchia Paolo 
Published: April 2021

Objective:
Ambulatory blood pressure (ABP) monitoring (ABPM) is currently performed for stratification of risk in hypertension. However, in clinical practice interest is focused on average ABP whereas little attention is paid to other ABPM parameters. Previous data have been obtained mainly from populations including elderly individuals, while little is known on the clinical significance of ABPM data in young individuals. Aim of the present study was to investigate whether and to what extent parameters other than average ABP are associated with CVE in individuals <= 45 years of age.

Design and method:
We performed ABPM in 2356 young-to-middle-age participants enrolled in 2 prospective studies in Italy (HARVEST and PIUMA). Mean age was 35.6 ± 7.6 years and mean BP was 143.3 ± 15.7/93.5 ± 10.6 mmHg. The ABPM parameters of interest were average 24 h systolic BP (SBP), 24 h systolic SD, and 24 h SBP diurnal rhythm. Participants were grouped according to whether they had high or low average 24 h SBP (cutoff, 130 mmHg), high or low systolic SD (cutoff, 12.8 mmHg), and were dippers or nondippers (cutoff 10% nocturnal decline). All parameters were included simultaneously in the same Cox models. Hazard ratios (HR) were adjusted for traditional risk factors.

Results:
During a median follow-up of 12.4 years, 164 CVE were observed. All ABPM parameters were independent predictors of the endpoints. However, a higher risk was observed for non dipping (HR,2.4; 95%CI,1.6–3.6; p < 0.0001) and for high SD (HR,2.0; 1.4–2.8; p = 0.0002) than for high average SBP (HR,1.5; 1.1–2.2; p = 0.019). Compared to dippers with low average SBP, nondippers with high average SBP had a HR of 3.2 (95%CI, 2.2–5.2). Compared to participants with low SD and low average SBP, participants with high average SBP and high SD had a HR of 2.8 (2.7–4.6). Similar results were obtained in the 1780 hypertensives and when the ABPM parameters were used as continuous variables.

Conclusions:
In young-to-middle-age subjects, dipping pattern and short-term BP variability are strong predictors of adverse outcome on top of average 24-hour BP. These two parameters should always be included in the stratification of risk when young hypertensive patients are assessed with ABPM.
SEASONAL VARIATION OF NIGHTIME HOME BLOOD PRESSURE AND ITS ASSOCIATION WITH TARGET ORGAN DAMAGE: THE J-HOP NOCTURNAL BLOOD PRESSURE STUDY
Authors: Narita Keisuke , Hoshide Satoshi , Kario Kazuomi 
Published: April 2021

Objective:
Although seasonal variation of nighttime home blood pressure (BP) was reported as higher in summer than winter, seasonal differences in the association of nighttime home BP with target organ damage (TOD) remains unclear. Hence, we assessed the seasonal variation of nighttime home BP and its association with TOD using a dataset of the Japan Morning Home-Surge BP (J-HOP) Nocturnal BP study.

Design and method:
This is a cross-sectional, post-hoc analysis using the dataset of the J-HOP Nocturnal BP study, which recruited patients with a history of or risk factors of cardiovascular disease. Participants underwent consecutive 14-day home BP measurements (morning and evening) and nighttime home BP measurements (a.m. 2, 3, and 4). Urine albumin creatinine ratio (UACR) and serum-brain natriuretic peptide (BNP) were collected at enrollment.

Results:
Among 2545 participants (age, 63.3 ± 10.3 yrs; antihypertensive medication use 82.6%), 629, 596, 719, and 601 participants were enrolled in spring, summer, autumn, and winter, respectively. Nighttime home systolic/diastolic BP (SBP/DBP) were higher in summer than in winter (SBP/DBP in summer, 123.3 ± 14.6/70.4 ± 8.9 mmHg; vs. in winter, 119.3 ± 14.0/69.1 ± 8.4 mmHg, each p value < 0.05 after adjusted with Bonferroni collection in each season), and the prevalence of riser pattern was also higher in summer than in winter (in summer, 27.2%; vs. in winter, 10.1%, p < 0.05). When the interaction between BP parameters and each season for the association with TOD was assessed, an association between riser pattern and UACR and an association between nighttime home DBP and BNP were stronger in winter compared to those in other seasons (both p for interaction < 0.05).

Conclusions:
In the present study, we revealed the association of nighttime home BP and TOD was stronger in winter than in other seasons.