circRNADisease v2.0: an updated resource for high-quality experimentally supported circRNA-disease associations.

circRNADisease v2.0 is an enhanced and reliable database that offers experimentally verified relationships between circular RNAs (circRNAs) and various diseases. It is accessible at http://cgga.org.cn/circRNADisease/ or http://cgga.org.cn:9091/circRNADisease/. The database currently includes 6998 circRNA-disease entries across multiple species, representing a remarkable 19.77-fold increase compared to the previous version. This expansion consists of a substantial rise in the number of circRNAs (from 330 to 4246), types of diseases (from 48 to 330) and covered species (from human only to 12 species). Furthermore, a new section has been introduced in the database, which collects information on circRNA-associated factors (genes, proteins and microRNAs), molecular mechanisms (molecular pathways), biological functions (proliferation, migration, invasion, etc.), tumor and/or cell line and/or patient-derived xenograft (PDX) details, and prognostic evidence in diseases. In addition, we identified 7 159 865 relationships between mutations and circRNAs among 30 TCGA cancer types. Due to notable enhancements and extensive data expansions, the circRNADisease 2.0 database has become an invaluable asset for both clinical practice and fundamental research. It enables researchers to develop a more comprehensive understanding of how circRNAs impact complex diseases.

Comparison of two single-pill dual combination antihypertensive therapies in Chinese patients: a randomized, controlled trial.

BACKGROUND: Current hypertension guidelines recommend combination of an angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker with a calcium-channel blocker or thiazide diuretic as initial antihypertensive therapy in patients with monotherapy uncontrolled hypertension. However, to what extent these two different combinations are comparable in blood pressure (BP)-lowering efficacy and safety remains under investigation, especially in the Chinese population. We investigated the BP-lowering efficacy and safety of the amlodipine/benazepril and benazepril/hydrochlorothiazide dual therapies in Chinese patients. METHODS: In a multi-center, randomized, actively controlled, parallel-group trial, we enrolled patients with stage 1 or 2 hypertension from July 2018 to June 2021 in 20 hospitals and community health centers across China. Of the 894 screened patients, 560 eligible patients were randomly assigned to amlodipine/benazepril 5/10 mg (n = 282) or benazepril/hydrochlorothiazide 10/12.5 mg (n = 278), with 213 and 212 patients, respectively, who completed the study and had a valid repeat ambulatory BP recording during follow-up and were included in the efficacy analysis. The primary outcome was the change from baseline to 24 weeks of treatment in 24-h ambulatory systolic BP. Adverse events including symptoms and clinically significant changes in physical examinations and laboratory findings were recorded for safety analysis. RESULTS: In the efficacy analysis (n = 425), the primary outcome, 24-h ambulatory systolic BP reduction, was - 13.8 ± 1.2 mmHg in the amlodipine/benazepril group and - 12.3 ± 1.2 mmHg in the benazepril/hydrochlorothiazide group, with a between-group difference of - 1.51 (p = 0.36) mmHg. The between-group differences for major secondary outcomes were - 1.47 (p = 0.18) in 24-h diastolic BP, - 2.86 (p = 0.13) and - 2.74 (p = 0.03) in daytime systolic and diastolic BP, and - 0.45 (p = 0.82) and - 0.93 (p = 0.44) in nighttime systolic and diastolic BP. In the safety analysis (n = 560), the incidence rate of dry cough was significantly lower in the amlodipine/benazepril group than in the benazepril/hydrochlorothiazide group (5.3% vs 10.1%, p = 0.04). CONCLUSIONS: The amlodipine/benazepril and benazepril/hydrochlorothiazide dual therapies were comparable in ambulatory systolic BP lowering. The former combination, compared with the latter, had a greater BP-lowering effect in the daytime and a lower incidence rate of dry cough. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03682692. Registered on 18 September 2018.

C-atrial natriuretic peptide (ANP)4-23 attenuates renal fibrosis in deoxycorticosterone-acetate-salt hypertensive mice.

Epithelial-mesenchymal transition (EMT) plays a critical role in hypertension-induced renal fibrosis, a final pathway that leads to end-stage renal failure. C-Atrial natriuretic peptide (ANP)4-23, a specific agonist of natriuretic peptide receptor-C (NPR-C), has been reported to have protective effects against hypertension. However, the role of C-ANP4-23 in hypertension-associated renal fibrosis has not yet been elucidated. In this study, mice were randomly divided into SHAM group, DOCA-salt group and DOCA-salt + C-ANP4-23 group. Renal morphology changes, renal function and fibrosis were detected. Human proximal tubular epithelial cells (HK2) stimulated by aldosterone were used for cell function and mechanism study. The DOCA-salt treated mice exhibited hypertension, kidney fibrosis and renal dysfunction, which were attenuated by C-ANP4-23. Moreover, C-ANP4-23 inhibited DOCA-salt treatment-induced renal EMT as evidenced by decrease of the mesenchymal marker alpha-smooth muscle actin (ACTA2) and vimentin and increase of epithelial cell marker E-cadherin. In HK2 cells, aldosterone induced EMT response, which was also suppressed by C-ANP4-23. The key transcription factors (twist, snail, slug and ZEB1) involved in EMT were increased in the kidney of DOCA-salt-treated mice, which were also suppressed by C-ANP4-23. Mechanistically, C-ANP4-23 inhibited the aldosterone-induced translocation of MR from cytosol to nucleus without change of MR expression. Furthermore, C-ANP4-23 rescued the enhanced expression of NADPH oxidase (NOX) 4 and oxidative stress after aldosterone stimulation. Aldosterone-induced Akt and Erk1/2 activation was also suppressed by C-ANP4-23. Our data suggest that C-ANP4-23 attenuates renal fibrosis, likely through inhibition of MR activation, enhanced oxidative stress and Akt and Erk1/2 signaling pathway.

Atrial Fibrillation and Dementia: A Report From the AF-SCREEN International Collaboration.

Growing evidence suggests a consistent association between atrial fibrillation (AF) and cognitive impairment and dementia that is independent of clinical stroke. This report from the AF-SCREEN International Collaboration summarizes the evidence linking AF to cognitive impairment and dementia. It provides guidance on the investigation and management of dementia in patients with AF on the basis of best available evidence. The document also addresses suspected pathophysiologic mechanisms and identifies knowledge gaps for future research. Whereas AF and dementia share numerous risk factors, the association appears to be independent of these variables. Nevertheless, the evidence remains inconclusive regarding a direct causal effect. Several pathophysiologic mechanisms have been proposed, some of which are potentially amenable to early intervention, including cerebral microinfarction, AF-related cerebral hypoperfusion, inflammation, microhemorrhage, brain atrophy, and systemic atherosclerotic vascular disease. The mitigating role of oral anticoagulation in specific subgroups (eg, low stroke risk, short duration or silent AF, after successful AF ablation, or atrial cardiopathy) and the effect of rhythm versus rate control strategies remain unknown. Likewise, screening for AF (in cognitively normal or cognitively impaired patients) and screening for cognitive impairment in patients with AF are debated. The pathophysiology of dementia and therapeutic strategies to reduce cognitive impairment warrant further investigation in individuals with AF. Cognition should be evaluated in future AF studies and integrated with patient-specific outcome priorities and patient preferences. Further large-scale prospective studies and randomized trials are needed to establish whether AF is a risk factor for cognitive impairment, to investigate strategies to prevent dementia, and to determine whether screening for unknown AF followed by targeted therapy might prevent or reduce cognitive impairment and dementia.

Dual endothelin antagonist aprocitentan for resistant hypertension (PRECISION): a multicentre, blinded, randomised, parallel-group, phase 3 trial.

BACKGROUND: Resistant hypertension is associated with increased cardiovascular risk. The endothelin pathway has been implicated in the pathogenesis of hypertension, but it is currently not targeted therapeutically, thereby leaving this relevant pathophysiological pathway unopposed with currently available drugs. The aim of the study was to assess the blood pressure lowering efficacy of the dual endothelin antagonist aprocitentan in patients with resistant hypertension. METHODS: PRECISION was a multicentre, blinded, randomised, parallel-group, phase 3 study, which was done in hospitals or research centres in Europe, North America, Asia, and Australia. Patients were eligible for randomisation if their sitting systolic blood pressure was 140 mm Hg or higher despite taking standardised background therapy consisting of three antihypertensive drugs, including a diuretic. The study consisted of three sequential parts: part 1 was the 4-week double-blind, randomised, and placebo-controlled part, in which patients received aprocitentan 12·5 mg, aprocitentan 25 mg, or placebo in a 1:1:1 ratio; part 2 was a 32-week single (patient)-blind part, in which all patients received aprocitentan 25 mg; and part 3 was a 12-week double-blind, randomised, and placebo-controlled withdrawal part, in which patients were re-randomised to aprocitentan 25 mg or placebo in a 1:1 ratio. The primary and key secondary endpoints were changes in unattended office systolic blood pressure from baseline to week 4 and from withdrawal baseline to week 40, respectively. Secondary endpoints included 24-h ambulatory blood pressure changes. The study is registered on ClinicalTrials.gov, NCT03541174. FINDINGS: The PRECISION study was done from June 18, 2018, to April 25, 2022. 1965 individuals were screened and 730 were randomly assigned. Of these 730 patients, 704 (96%) completed part 1 of the study; of these, 613 (87%) completed part 2 and, of these, 577 (94%) completed part 3 of the study. The least square mean (SE) change in office systolic blood pressure at 4 weeks was -15·3 (SE 0·9) mm Hg for aprocitentan 12·5 mg, -15·2 (0·9) mm Hg for aprocitentan 25 mg, and -11·5 (0·9) mm Hg for placebo, for a difference versus placebo of -3·8 (1·3) mm Hg (97·5% CI -6·8 to -0·8, p=0·0042) and -3·7 (1·3) mm Hg (-6·7 to -0·8; p=0·0046), respectively. The respective difference for 24 h ambulatory systolic blood pressure was -4·2 mm Hg (95% CI -6·2 to -2·1) and -5·9 mm Hg (-7·9 to -3·8). After 4 weeks of withdrawal, office systolic blood pressure significantly increased with placebo versus aprocitentan (5·8 mm Hg, 95% CI 3·7 to 7·9, p<0·0001). The most frequent adverse event was mild-to-moderate oedema or fluid retention, occurring in 9%, 18%, and 2% for patients receiving aprocitentan 12·5 mg, 25 mg, and placebo, during the 4-week double-blind part, respectively. This event led to discontinuation in seven patients treated with aprocitentan. During the trial, a total of 11 treatment-emergent deaths occurred, none of which were regarded by the investigators to be related to study treatment. INTERPRETATION: In patients with resistant hypertension, aprocitentan was well tolerated and superior to placebo in lowering blood pressure at week 4 with a sustained effect at week 40. FUNDING: Idorsia Pharmaceuticals and Janssen Biotech.

Mitogen-Activated Protein Kinases Mediate Adventitial Fibroblast Activation and Neointima Formation via GATA4/Cyclin D1 Axis.

PURPOSE: Activation of mitogen-activated protein kinases (MAPKs) by pathological stimuli participates in cardiovascular diseases. Dysfunction of adventitial fibroblast has emerged as a critical regulator in vascular remodeling, while the potential mechanism remains unclear. In this study, we sought to determine the effect of different activation of MAPKs in adventitial fibroblast contributing to neointima formation. METHODS: Balloon injury procedure was performed in male 12-week-old Sprague-Dawley rats. After injury, MAPK inhibitors were applied to the adventitia of injured arteries to suppress MAPK activation. Adventitial fibroblasts were stimulated by platelet-derived growth factor-BB (PDGF-BB) with or without MAPK inhibitors. RNA sequencing was performed to investigate the change of pathway and cell function. Wound healing, transwell assay, and flow cytometry were used to analyze adventitial fibroblast function. RESULTS: Phosphorylation of p38, c-Jun N-terminal kinase (JNK), and extracellular regulated kinases 1/2 (ERK1/2) was increased in injured arteries after balloon injury. In primary culture of adventitial fibroblasts, PDGF-BB increased phosphorylation of p38, JNK, ERK1/2, and extracellular regulated kinase 5 (ERK5) in a short time, which was normalized by their inhibitors respectively. Compared with the injury group, perivascular administration of four MAPK inhibitors significantly attenuated neointima formation by quantitative analysis of neointimal area, intima to media (I/M) ratio, and lumen area. RNA sequencing of adventitial fibroblasts treated with PDGF-BB with or without four inhibitors demonstrated differentially expressed genes involved in multiple biological processes, including cell adhesion, proliferation, migration, and inflammatory response. Wound healing and transwell assays showed that four inhibitors suppressed PDGF-BB-induced adventitial fibroblast migration. Cell cycle analysis by flow cytometry demonstrated that JNK, ERK1/2, and ERK5 but not p38 inhibitor blocked PDGF-BB-induced G1 phase release associated with decrease expression of cell cycle protein Cyclin D1 and transcription factor GATA4. Moreover, four inhibitors decreased macrophage infiltration into adventitia and monocyte chemoattractant protein-1 (MCP-1) expression. CONCLUSION: These results suggest that MAPKs differentially regulate activation of adventitial fibroblast through GATA4/Cyclin D1 axis that participates in neointima formation.

Angiotensin-converting enzyme 2 in human plasma and lung tissue.

PURPOSE: We investigated plasma angiotensin-converting enzyme 2 (ACE2) concentration in a population sample and the ACE2 expression quantitated with the diaminobenzidine mean intensity in the lung tissue in patients who underwent lung surgery. MATERIALS AND METHODS: The study participants were recruited from a residential area in the suburb of Shanghai for the plasma ACE2 concentration study (n = 503) and the lung tissue samples were randomly selected from the storage in Ruijin Hospital (80 men and 78 age-matched women). RESULTS: In analyses adjusted for covariables, men had a significantly higher plasma ACE2 concentration (1.21 vs. 0.98 ng/mL, p = 0.027) and the mean intensity of ACE2 in the lung tissue (55.1 vs. 53.9 a.u., p = 0.037) than women. With age increasing, plasma ACE2 concentration decreased (p = 0.001), while the mean intensity of ACE2 in the lung tissue tended to increase (p = 0.087). Plasma ACE2 concentration was higher in hypertension than normotension, especially treated hypertension (1.23 vs. 0.98 ng/mL, p = 0.029 vs. normotension), with no significant difference between users of RAS inhibitors and other classes of antihypertensive drugs (p = 0.64). There was no significance of the mean intensity of ACE2 in the lung tissue between patients taking and those not taking RAS inhibitors (p = 0.14). Neither plasma ACE2 concentration nor the mean intensity of ACE2 in the lung tissue differed between normoglycemia and diabetes (p ≥ 0.20). CONCLUSION: ACE2 in the plasma and lung tissue showed divergent changes according to several major characteristics of patients.Plain language summary What is the context? • The primary physiological function of ACE2 is the degradation of angiotensin I and II to angiotensin 1-9 and 1-7, respectively. • ACE2 was found to behave as a mediator of the severe acute respiratory syndrome coronavirus (SARS) infection. • There is little research on ACE2 in humans, especially in the lung tissue. • In the present report, we investigated plasma ACE2 concentration and the ACE2 expression quantitated with the diaminobenzidine mean intensity in the lung tissue respectively in two study populations. What is new? • Our study investigated both circulating and tissue ACE2 in human subjects. The main findings were: • In men as well as women, plasma ACE2 concentration was higher in younger than older participants, whereas the mean intensity of ACE2 in the lung tissue increase with age increasing. • Compared with normotension, hypertensive patients had higher plasma ACE2 concentration but similar mean intensity of ACE2 in the lung tissue. • Neither plasma ACE2 concentration nor lung tissue ACE2 expression significantly differed between users of RAS inhibitors and other classes of antihypertensive drugs. What is the impact? • ACE2 in the plasma and lung tissue showed divergent changes according to several major characteristics, such as sex, age, and treated and untreated hypertension. • A major implication is that plasma ACE2 concentration might not be an appropriate surrogate for the ACE2 expression in the lung tissue, and hence not a good predictor of SARS-COV-2 infection or fatality.

A hepatocyte differentiation model reveals two subtypes of liver cancer with different oncofetal properties and therapeutic targets.

Clinical observation of the association between cancer aggressiveness and embryonic development stage implies the importance of developmental signals in cancer initiation and therapeutic resistance. However, the dynamic gene expression during organogenesis and the master oncofetal drivers are still unclear, which impeded the efficient elimination of poor prognostic tumors, including human hepatocellular carcinoma (HCC). In this study, human embryonic stem cells were induced to differentiate into adult hepatocytes along hepatic lineages to mimic liver development in vitro. Combining transcriptomic data from liver cancer patients with the hepatocyte differentiation model, the active genes derived from different hepatic developmental stages and the tumor tissues were selected. Bioinformatic analysis followed by experimental assays was used to validate the tumor subtype-specific oncofetal signatures and potential therapeutic values. Hierarchical clustering analysis revealed the existence of two subtypes of liver cancer with different oncofetal properties. The gene signatures and their clinical significance were further validated in an independent clinical cohort and The Cancer Genome Atlas database. Upstream activator analysis and functional screening further identified E2F1 and SMAD3 as master transcriptional regulators. Small-molecule inhibitors specifically targeting the oncofetal drivers extensively down-regulated subtype-specific developmental signaling and inhibited tumorigenicity. Liver cancer cells and primary HCC tumors with different oncofetal properties also showed selective vulnerability to their specific inhibitors. Further precise targeting of the tumor initiating steps and driving events according to subtype-specific biomarkers might eliminate tumor progression and provide novel therapeutic strategy.

Associations of Early Systolic Blood Pressure Control and Outcome After Thrombolysis-Eligible Acute Ischemic Stroke: Results From the ENCHANTED Study.

BACKGROUND AND PURPOSE: In thrombolysis-eligible patients with acute ischemic stroke, there is uncertainty over the most appropriate systolic blood pressure (SBP) lowering profile that provides an optimal balance of potential benefit (functional recovery) and harm (intracranial hemorrhage). We aimed to determine relationships of SBP parameters and outcomes in thrombolyzed acute ischemic stroke patients. METHODS: Post hoc analyzes of the ENCHANTED (Enhanced Control of Hypertension and Thrombolysis Stroke Study), a partial-factorial trial of thrombolysis-eligible and treated acute ischemic stroke patients with high SBP (150-180 mm Hg) assigned to low-dose (0.6 mg/kg) or standard-dose (0.9 mg/kg) alteplase and intensive (target SBP, 130-140 mm Hg) or guideline-recommended (target SBP <180 mm Hg) treatment. All patients were followed up for functional status and serious adverse events to 90 days. Logistic regression models were used to analyze 3 SBP summary measures postrandomization: attained (mean), variability (SD) in 1-24 hours, and magnitude of reduction in 1 hour. The primary outcome was a favorable shift on the modified Rankin Scale. The key safety outcome was any intracranial hemorrhage. RESULTS: Among 4511 included participants (mean age 67 years, 38% female, 65% Asian) lower attained SBP and smaller SBP variability were associated with favorable shift on the modified Rankin Scale (per 10 mm Hg increase: odds ratio, 0.76 [95% CI, 0.71-0.82]; P<0.001 and 0.86 [95% CI, 0.76-0.98]; P=0.025) respectively, but not for magnitude of SBP reduction (0.98, [0.93-1.04]; P=0.564). Odds of intracranial hemorrhage was associated with higher attained SBP and greater SBP variability (1.18 [1.06-1.31]; P=0.002 and 1.34 [1.11-1.62]; P=0.002) but not with magnitude of SBP reduction (1.05 [0.98-1.14]; P=0.184). CONCLUSIONS: Attaining early and consistent low levels in SBP <140 mm Hg, even as low as 110 to 120 mm Hg, over 24 hours is associated with better outcomes in thrombolyzed acute ischemic stroke patients. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01422616.

Treatment of Masked Hypertension with a Chinese Herbal Formula: A Randomized, Placebo-Controlled Trial.

BACKGROUND: Masked hypertension is associated with adverse cardiovascular outcomes. Nonetheless, no randomized controlled trials exist in the treatment of masked hypertension. The aim of this randomized, placebo-controlled trial was to investigate the efficacy and safety of blood pressure (BP)-lowering treatment with a Chinese herbal formula, gastrodia-uncaria granules, in patients with masked hypertension. METHODS: Patients with an office BP of <140/90 mm Hg and daytime ambulatory BP of 135 to 150 mm Hg systolic or 85 to 95 mm Hg diastolic were randomly assigned 1:1 to the treatment of gastrodia-uncaria granules or placebo 5 to 10 g twice daily for 4 weeks. The primary efficacy variable was the change in daytime ambulatory BP. RESULTS: At baseline, office and daytime BP of the 251 participants (mean age, 50.4 years; 53.4% men; mean body mass index 24.5 kg/m2; and 2.8%, 1.6%, and 30.7% with cardiovascular disease, diabetes, and smoking, respectively) averaged 129/82 and 135/89 mm Hg, respectively. In the intention-to-treat analysis, daytime systolic/diastolic BP was reduced by 5.44/3.39 and 2.91/1.60 mm Hg in the gastrodia-uncaria granules and placebo groups, respectively. The between-group difference in BP reductions was significant for the daytime (2.52/1.79 mm Hg; P≤0.025) and 24-hour BP (2.33/1.49 mm Hg; P≤0.012), but not for the clinic and nighttime BPs (P≥0.162). The per-protocol analysis in 229 patients produced similar results. Only 1 adverse event (sleepiness during the day) was reported, and no serious adverse event occurred. CONCLUSIONS: BP-lowering treatment with Chinese traditional medicine gastrodia-uncaria granules is efficacious for patients with masked hypertension. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02156024.

Alcohol consumption in relation to cardiovascular and non-cardiovascular mortality in an elderly male Chinese population.

BACKGROUND: We investigated the association of alcohol consumption with cardiovascular and non-cardiovascular mortality in elderly Chinese men. METHODS: Our participants were recruited from residents living in a suburban town of Shanghai (≥60 years of age, n = 1702). Alcohol intake was classified as non-drinkers, past drinkers (stopped drinking for ≥12 months), and current light-to-moderate (1 to 299 g/week) and heavy drinkers (≥300 g/week). Alcoholic beverages were classified as beer/wine, rice aperitif and liquor/mix drinking. RESULTS: During 5.9 years (median) of follow-up, all-cause, cardiovascular and non-cardiovascular deaths occurred in 211, 98 and 113 participants, respectively. The corresponding incidence rates were 23.6/1000, 10.9/1000 and 12.6/1000 person-years, respectively. Both before and after adjustment for confounding factors, compared with non-drinkers (n = 843), past drinkers (n = 241), but not the current light-to-moderate (n = 241) or heavy drinkers (n = 377), had a higher risk of all-cause (adjusted hazard ratio [HR] 1.90, 95% confidence interval [CI] 1.35-2.68, P = 0.0003) and non-cardiovascular mortality (HR 2.46, 95% CI 1.55-3.91, P = 0.0001). Similar trends were observed for cardiovascular mortality (HR 1.44, 95% CI 0.85-2.44, P = 0.18). In similar unadjusted and adjusted analyses, compared with the current beer/wine drinkers (n = 203), liquor/mix drinkers (n = 142), but not aperitif drinkers (n = 273), had a significantly higher risk of all-cause (HR 3.07, 95% CI 1.39-6.79, P = 0.006), and cardiovascular mortality (HR 10.49, 95% CI 2.00-55.22, P = 0.006). Similar trends were observed for non-cardiovascular mortality (HR 1.94, 95% CI 0.73-5.16, P = 0.18). CONCLUSIONS: Our study showed risks of mortality associated with past drinking and liquor drinking in the elderly Chinese men.

Treatment effect of lacidipine and amlodipine on clinic and ambulatory blood pressure and arteria stiffness in a randomised double-blind trial.

PURPOSE: In a randomised, double-blind trial, we investigated effects of lacidipine on clinic and ambulatory blood pressure (BP) and arterial stiffness in patients with mild-to-moderate hypertension, as compared with amlodipine. MATERIALS AND METHODS: Previously untreated and treated patients (n = 269, 50-80 years of age) with clinic hypertension (a clinic systolic/diastolic BP 140-180/<110 mmHg and <160/100 mmHg, respectively) were randomly assigned to double-dummy treatment with lacidipine (4-6 mg/day) or amlodipine (5-7.5 mg/day) for 20 weeks. The primary efficacy variable was the change in 24-h ambulatory systolic BP at 20 weeks of treatment. Arterial stiffness was measured as brachial-ankle pulse wave velocity (PWV). RESULTS: After 20 weeks of treatment, 24-h systolic BP decreased from 141.3 ± 14.0 and 138.3 ± 12.8 mmHg at baseline, respectively, in the lacidipine (n = 134) and amlodipine groups (n = 135), by a least square mean (±SE) change of 15.2 ± 1.3 and 15.5 ± 1.3 mmHg, respectively, with a between-group difference (95% confidence interval [CI]) of 0.3 mmHg (-3.4 to 4.1, p = 0.86). Similar results were observed for other ambulatory BP components and clinic BP. Clinic and ambulatory pulse rate did not significantly change in either group (p ≥ 0.21). PWV decreased significantly (p < 0.001) from baseline in both groups, with a non-significant between-group difference of 0.24 m/s (p = 0.45). The incidence rate of adverse events was 30.3% (n = 40) and 27.5% (n = 36) in the lacidipine and amlodipine groups, respectively (p = 0.61). No serious adverse event occurred in the trial. CONCLUSIONS: Lacidipine effectively lowers clinic and ambulatory BP in patients with mild-to-moderate hypertension and significantly improves arterial stiffness, similarly as amlodipine.

Age-stratified association of blood pressure with albuminuria and left ventricular hypertrophy in patients with hypertension and diabetes mellitus.

PURPOSE: We investigated associations of blood pressure (BP) with albuminuria and left ventricular hypertrophy (LVH) in young, middle and older aged patients with hypertension and/or diabetes mellitus. MATERIALS & METHODS: Study participants were treated patients with hypertension or diabetes, enrolled in a China nationwide registry. The 2510 patients were classified into young (<45 years, n = 345), middle (45-64 years, n = 1383) and older (≥65 years, n = 782) age groups. Clinic BP was measured three times consecutively on each of the two clinic visits. These six readings were averaged for analyses. Albuminuria was defined as a urinary albumin-to-creatinine ratio of ≥30 mg/g. LVH was assessed by the electrocardiogram (ECG) Cornell product and voltage methods. RESULTS: The prevalence of albuminuria and ECG-LVH was 17.8 and 6.5%, respectively. Mean (±SD) systolic/diastolic BP was 132.0 ± 16.5/85.2 ± 11.9 mmHg, 136.8 ± 17.9/81.7 ± 11.2 mmHg, and 139.8 ± 16.7/75.8 ± 10.4 mmHg in the young, middle and older age groups. In the young age group, the prevalence of albuminuria increased from 8.8% in systolic/diastolic BP <120/80 mmHg to 14.6, 16.0% and 16.5% in 120-129/80-84, 130-139/85-89 and ≥140/90 mmHg, respectively. The corresponding values were 8.9, 7.0, 18.1 and 22.2%, respectively, in the middle age group, and 21.2, 15.5, 16.4 and 24.4%, respectively, in the older age group. Adjusted analyses confirmed the J-shaped relation between BP and albuminuria in the older but not young age group. The prevalence of ECG-LVH was significantly (p for trend ≤0.04) higher with increasing BP similarly in all age groups. CONCLUSIONS: The association between BP and organ damage seems to differ in young, middle and older aged patients for albuminuria but not ECG-LVH.

Serum uric acid change in relation to antihypertensive therapy with the dihydropyridine calcium channel blockers.

PURPOSE: We investigated serum uric acid changes in relation to the achieved clinic and ambulatory blood pressure after 8 weeks of antihypertensive therapy with two dihydropyridine calcium channel blockers. MATERIALS AND METHODS: The study participants were patients with clinic and ambulatory hypertension, enrolled in a randomised controlled trial that compared amlodipine (5-10 mg, n = 215) and nifedipine gastrointestinal therapeutic system (GITS, 30-60 mg, n = 203). Hyperuricaemia was defined as a serum uric acid concentration of ≥420 µmol/L in men and ≥360 µmol/L in women. Analysis of covariance and multiple regression analyses were performed to study the associations between serum uric acid changes and the achieved clinic and ambulatory blood pressure during follow-up. RESULTS: At baseline, 67 (16.0%) of the 418 patients had hyperuricaemia. Antihypertensive treatment reduced clinic and 24-h daytime and night-time systolic/diastolic blood pressure by a mean (±standard error [SE]) change of -17.4 ± 0.6/-8.6 ± 0.4 mm Hg and -13.7 ± 0.5/-8.3 ± 0.3 mm Hg, -13.8 ± 0.6/-8.4 ± 0.4 mm Hg, and -12.7 ± 0.7/-8.0 ± 0.4 mm Hg, respectively. Antihypertensive treatment reduced serum uric acid by a mean (±SE) change of -9.3 ± 2.8 µmol/L. The serum uric acid changes differed according to the achieved clinic and ambulatory blood pressure, and were statistically significant (mean ± SE -20.6 ± 6.6 to -10.7 ± 2.9 µmol/L, p ≤ 0.04) at the systolic/diastolic ranges of 130-139/≥90 mm Hg in clinic pressure, and <130/75-84 mm Hg, <145/80-84 mm Hg and <120/65-69 mm Hg in 24-h, daytime and night-time ambulatory pressure. CONCLUSION: Our study showed that antihypertensive therapy with a dihydropyridine calcium channel blocker was associated with reduced serum uric acid, especially when 24-h ambulatory systolic blood pressure was controlled.

Ambulatory blood pressure in relation to interaction between dietary sodium intake and serum uric acid in the young.

PURPOSE: We hypothesise that dietary sodium intake interacts with serum uric acid to influence blood pressure (BP) in children and adolescents. In the present study, we investigated ambulatory BP in relation to hyperuricaemia, dietary sodium intake and their interaction in children and adolescents with hypertension. MATERIALS AND METHODS: A total of 616 study participants were 10-24 years old and had primary hypertension diagnosed after admission in a specialised inpatient ward. Ambulatory BP monitoring was performed during hospitalisation. 24-h urine was collected for measurements of electrolytes. Hyperuricaemia was defined as a serum uric acid of ≥327.25 µmol/L in patients <18 years old and of ≥420 and ≥360 µmol/L, respectively, in male and female patients ≥18 years old. RESULTS: In adjusted analyses, patients with hyperuricaemia (n = 283), compared with those with normal serum uric acid, had similar 24-h systolic BP (131.7 mmHg, p = 0.54) and a significantly (p ≤ 0.005) lower 24-h diastolic BP (77.5 vs. 80.9 mmHg) and higher 24-h pulse pressure (54.2 vs. 51.7 mmHg). In similar adjusted analyses, 24-h ambulatory pulse pressure, but not systolic/diastolic BP (p ≥ 0.12), significantly differed across the quartile distributions of urinary sodium excretion (p for trend ≤ 0.04). Further adjusted analyses showed significant (p ≤ 0.04) interaction between serum uric acid and urinary sodium excretion in relation to 24-h systolic BP. In patients with hyperuricaemia (p = 0.04), but not those with normal serum uric acid (p = 0.13), 24-h systolic BP was significantly associated with urinary sodium excretion, with a 6.5 ± 2.1 mmHg difference between quartiles 4 and 1. Similar results were observed for daytime and night-time BP and pulse pressure. CONCLUSIONS: Both hyperuricaemia and higher dietary sodium intake were associated with higher pulse pressure, and their interaction further heightened systolic BP.

Continuous positive airway pressure adherence and blood pressure lowering in patients with obstructive sleep apnoea syndrome and nocturnal hypertension.

PURPOSE: We investigated continuous positive airway pressure (CPAP) adherence and its association with the blood pressure (BP) and pulse rate changes in patients with obstructive sleep apnoea syndrome (OSAS) and hypertension. MATERIALS AND METHODS: In a single-blind trial, patients were randomly assigned to CPAP or sham CPAP treatment for 3 months. We performed clinic, ambulatory and home BP measurements at baseline and during follow-up. CPAP adherence was assessed as the CPAP frequency per week and time per night. Non-adherence was defined as a CPAP use for <5 days/week or <4 h/night. RESULTS: In the CPAP (n = 26) and sham CPAP groups (n = 21), the CPAP frequency was 5.5 and 4.8 days/week (p = 0.17), respectively, and the CPAP time was 5.0 and 4.1 h/night (p = 0.03), respectively. The corresponding prevalence of non-adherence was 46.2% and 66.7% (p = 0.16), respectively. The CPAP frequency but not time tended to be associated with the changes in BP and pulse rate at 3 months of follow-up, especially home systolic/diastolic BP in the CPAP group (3.2/1.3 mmHg greater reductions per 1 day increment, p ≤ 0.01). Adherent, compared with non-adherent patients, had greater reductions in BP or pulse rate at 3 months of follow-up. In the CPAP and sham CPAP groups combined, statistical significance was achieved for the adjusted between adherence and non-adherence differences in home systolic/diastolic BP (-5.0/-3.8 mmHg) and 24-h, daytime and night-time ambulatory pulse rate (-6.2, -7.8 and -4.4 beats/min, respectively, p ≤ 0.04). CONCLUSION: CPAP adherence was associated with the BP lowering and pulse rate slowing effects, especially the CPAP frequency.

May Measurement Month 2019: an analysis of blood pressure screening results from China.

To report the blood pressure (BP) data obtained in the May Measurement Month (MMM) 2019 in China. Study participants were recruited if ≥18 years of age and had ideally not had their BP measured for ≥1 year. BP was measured three times consecutively with a 1-min interval in the sitting position, using a validated electronic BP monitor. Trained volunteer investigators administered a questionnaire to collect information on lifestyle, medical history, and use of medications. The measurement was performed in 238 387 participants in 250 sites across 31 China provinces. The majority of screening took place in hospitals or clinics (78.7%), with 17.1% in outdoor public areas and 4.2% in other settings. The study participants included 127 853 women (53.6%) and had a mean (±SD) age of 48.9 ± 16.2 years. The mean (of readings two and three) systolic/diastolic BP was 121.8/73.8 mmHg. In all hypertensive patients (n = 66 181, 27.8%), the awareness, treatment, and control rates of hypertension were 51.5%, 48.4%, and 29.1%, respectively. Linear regression models showed differences in systolic and diastolic BP according to sex and age and several other major characteristics, such as previous stroke, myocardial infarction, and diabetes mellitus, antihypertensive medication use and known hypertension, previous hypertension in pregnancy and current pregnancy, alcohol intake and current smoking, and body mass index. The MMM 2019 campaign has been successful in measuring BP in a large member of participants in China.

Non-steroidal anti-inflammatory drug (NSAID) therapy in patients with hypertension, cardiovascular, renal or gastrointestinal comorbidities: joint APAGE/APLAR/APSDE/APSH/APSN/PoA recommendations.

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most commonly prescribed medications, but they are associated with a number of serious adverse effects, including hypertension, cardiovascular disease, kidney injury and GI complications. OBJECTIVE: To develop a set of multidisciplinary recommendations for the safe prescription of NSAIDs. METHODS: Randomised control trials and observational studies published before January 2018 were reviewed, with 329 papers included for the synthesis of evidence-based recommendations. RESULTS: Whenever possible, a NSAID should be avoided in patients with treatment-resistant hypertension, high risk of cardiovascular disease and severe chronic kidney disease (CKD). Before treatment with a NSAID is started, blood pressure should be measured, unrecognised CKD should be screened in high risk cases, and unexplained iron-deficiency anaemia should be investigated. For patients with high cardiovascular risk, and if NSAID treatment cannot be avoided, naproxen or celecoxib are preferred. For patients with a moderate risk of peptic ulcer disease, monotherapy with a non-selective NSAID plus a proton pump inhibitor (PPI), or a selective cyclo-oxygenase-2 (COX-2) inhibitor should be used; for those with a high risk of peptic ulcer disease, a selective COX-2 inhibitor plus PPI are needed. For patients with pre-existing hypertension receiving renin-angiotensin system blockers, empirical addition (or increase in the dose) of an antihypertensive agent of a different class should be considered. Blood pressure and renal function should be monitored in most cases. CONCLUSION: NSAIDs are a valuable armamentarium in clinical medicine, but appropriate recognition of high-risk cases, selection of a specific agent, choice of ulcer prophylaxis and monitoring after therapy are necessary to minimise the risk of adverse events.

Detection rate and treatment gap for atrial fibrillation identified through screening in community health centers in China (AF-CATCH): A prospective multicenter study.

BACKGROUND: Atrial fibrillation (AF) is underdiagnosed and especially undertreated in China. We aimed to investigate the prevalence of unknown and untreated AF in community residents (≥65 years old) and to determine whether an education intervention could improve oral anticoagulant (OAC) prescription. METHODS AND FINDINGS: We performed a single-time point screening for AF with a handheld single-lead electrocardiography (ECG) in Chinese residents (≥65 years old) in 5 community health centers in Shanghai from April to September 2017. Disease education and advice on referral to specialist clinics for OAC treatment were provided to all patients with actionable AF (newly detected or undertreated known AF) at the time of screening, and education was reinforced at 1 month. Follow-up occurred at 12 months. In total, 4,531 participants were screened (response rate 94.7%, mean age 71.6 ± 6.3 years, 44% male). Overall AF prevalence was 4.0% (known AF 3.5% [n = 161], new AF 0.5% [n = 22]). The 183 patients with AF were older (p < 0.001), taller (p = 0.02), and more likely to be male (p = 0.01), and they had a higher prevalence of cardiovascular disease than those without AF (p < 0.001). In total, 85% (155/183) of patients were recommended for OAC treatment by the established guidelines (CHA2DS2-VASc ≥ 2 for men; ≥ 3 for women). OAC prescription rate for known AF was 20% (28/138), and actionable AF constituted 2.8% of all those screened. At the 12-month follow-up in 103 patients (81% complete), despite disease education and advice on specialist referral, only 17 attended specialist clinics, and 4 were prescribed OAC. Of those not attending specialist clinics, 71 chose instead to attend community health centers or secondary hospital clinics, with none prescribed OAC, and 15 had no review. Of the 17 patients with new AF and a class 1 recommendation for OAC, only 3 attended a specialist clinic, and none were prescribed OAC. Of the 28 AF patients taking OAC at baseline, OAC was no longer taken in 4. Ischemic stroke (n = 2) or death (n = 3) occurred in 5/126 (4%), with none receiving OAC. As screening was performed at a single time point, some paroxysmal AF cases may have been missed; thus, the rate of new AF may be underestimated. CONCLUSIONS: We demonstrated a noticeable gap in AF detection and treatment in community-based elderly Chinese: actionable AF constituted a high proportion of those screened. Disease education and advice on specialist referral are insufficient to close the gap. Before more frequent or intensive screening for unknown AF could be recommended in China, greater efforts must be made to increase appropriate OAC therapy in known AF to prevent AF-related stroke.

Intensive blood pressure reduction with intravenous thrombolysis therapy for acute ischaemic stroke (ENCHANTED): an international, randomised, open-label, blinded-endpoint, phase 3 trial.

BACKGROUND: Systolic blood pressure of more than 185 mm Hg is a contraindication to thrombolytic treatment with intravenous alteplase in patients with acute ischaemic stroke, but the target systolic blood pressure for optimal outcome is uncertain. We assessed intensive blood pressure lowering compared with guideline-recommended blood pressure lowering in patients treated with alteplase for acute ischaemic stroke. METHODS: We did an international, partial-factorial, open-label, blinded-endpoint trial of thrombolysis-eligible patients (age ≥18 years) with acute ischaemic stroke and systolic blood pressure 150 mm Hg or more, who were screened at 110 sites in 15 countries. Eligible patients were randomly assigned (1:1, by means of a central, web-based program) within 6 h of stroke onset to receive intensive (target systolic blood pressure 130-140 mm Hg within 1 h) or guideline (target systolic blood pressure <180 mm Hg) blood pressure lowering treatment over 72 h. The primary outcome was functional status at 90 days measured by shift in modified Rankin scale scores, analysed with unadjusted ordinal logistic regression. The key safety outcome was any intracranial haemorrhage. Primary and safety outcome assessments were done in a blinded manner. Analyses were done on intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT01422616. FINDINGS: Between March 3, 2012, and April 30, 2018, 2227 patients were randomly allocated to treatment groups. After exclusion of 31 patients because of missing consent or mistaken or duplicate randomisation, 2196 alteplase-eligible patients with acute ischaemic stroke were included: 1081 in the intensive group and 1115 in the guideline group, with 1466 (67·4%) administered a standard dose among the 2175 actually given intravenous alteplase. Median time from stroke onset to randomisation was 3·3 h (IQR 2·6-4·1). Mean systolic blood pressure over 24 h was 144·3 mm Hg (SD 10·2) in the intensive group and 149·8 mm Hg (12·0) in the guideline group (p<0·0001). Primary outcome data were available for 1072 patients in the intensive group and 1108 in the guideline group. Functional status (mRS score distribution) at 90 days did not differ between groups (unadjusted odds ratio [OR] 1·01, 95% CI 0·87-1·17, p=0·8702). Fewer patients in the intensive group (160 [14·8%] of 1081) than in the guideline group (209 [18·7%] of 1115) had any intracranial haemorrhage (OR 0·75, 0·60-0·94, p=0·0137). The number of patients with any serious adverse event did not differ significantly between the intensive group (210 [19·4%] of 1081) and the guideline group (245 [22·0%] of 1115; OR 0·86, 0·70-1·05, p=0·1412). There was no evidence of an interaction of intensive blood pressure lowering with dose (low vs standard) of alteplase with regard to the primary outcome. INTERPRETATION: Although intensive blood pressure lowering is safe, the observed reduction in intracranial haemorrhage did not lead to improved clinical outcome compared with guideline treatment. These results might not support a major shift towards this treatment being applied in those receiving alteplase for mild-to-moderate acute ischaemic stroke. Further research is required to define the underlying mechanisms of benefit and harm resulting from early intensive blood pressure lowering in this patient group. FUNDING: National Health and Medical Research Council of Australia; UK Stroke Association; Ministry of Health and the National Council for Scientific and Technological Development of Brazil; Ministry for Health, Welfare, and Family Affairs of South Korea; Takeda.