ABSTRACT Mucin‐1 was reported be correlated with organ fibrosis. Pulse pressure amplification (PPA) was a marker of arterial stiffness. We investigate the association of serum mucin‐1 (CA15‐3) concentration with peripheral and central blood pressure and PPA in untreated Chinese patients. The study participants were outpatients who were suspected of hypertension, but had not been treated with antihypertensive medication for at least two weeks. Serum mucin‐1 (CA15‐3) concentration was measured by the enzyme‐linked immunosorbent assay method. PPA was the brachial‐to‐aortic pulse pressure ratio. The 1761 participants included 916 (52.0%) women, and 578 (32.8%) participants with clinic hypertension. Mean (±standard deviation [SD]) age was 51.3±10.6 years. After adjustment for confounders, higher serum mucin‐1 (CA15‐3) concentration was significantly associated with higher peripheral and central systolic and diastolic blood pressure ( p ≤0.009) and lower PPA ( p = 0.037). Among 428 participants with a PPA equal or greater than 130% at baseline, 185 progressed to be a lower PPA (<130%) during a median follow‐up of 4.65 years. Hazard ratio expressed the relative risk of lower PPA per 1 SD increment in the log transformed serum mucin‐1 (CA15‐3) concentration was 1.22 ( p = 0.027). In women but not in men, the risk of lower PPA was significantly higher with increased baseline serum mucin‐1 (CA15‐3) concentration ( p for interaction 0.015). Higher circulating mucin‐1 (CA15‐3) concentration was independently associated with higher peripheral and central blood pressure and lower PPA in untreated Chinese patients. It also correlated with the progression of arterial stiffness as indicated by a lower PPA, especially in women.

Background Current hypertension guidelines recommend either ambulatory or home blood pressure (BP) monitoring for the management of hypertension. How we should properly utilize these 2 out-of-office BP measurement techniques remains under investigation. Objectives The purpose of this study was to investigate ambulatory and home BP monitoring in the definition of BP phenotypes with regard to cardiovascular outcomes. Methods In a nationwide prospective cohort, baseline observations were collected from August 2009 to October 2017, with last follow-ups in July 2024. Results Among 4,935 participants (mean age 54.3 years), median follow-up time was 4.9 years. The incidence rate of all cardiovascular events (n = 256), stroke (n = 100), and cardiac events (n = 171) was significantly (P ≤ 0.001) higher in 2,894 treated (14.9, 5.9, and 9.7 per 1,000 person-years, respectively) than 2,041 untreated outpatients (4.5, 1.4, and 3.2 per 1,000 person-years, respectively). In untreated patients, the analyses adjusted for confounders and mutually one for another out-of-office BP measurement technique showed that ambulatory but not home (masked and sustained) hypertension was associated with a higher risk of cardiac events relative to normotension (HR: 9.01; 95% CI: 1.10-73.91; and HR: 9.74; 95% CI: 1.01-94.25, respectively). In treated patients, the similarly adjusted analyses showed that home but not ambulatory sustained uncontrolled hypertension was associated with a higher risk of all cardiovascular events (HR: 1.80; 95% CI: 1.12-2.92; P = 0.02) and stroke (HR: 2.32; 95% CI: 1.00-5.42; P = 0.05) relative to controlled hypertension. Conclusions Our study in young and middle-aged outpatients indicates a preferable role of ambulatory and home BP monitoring, respectively, in untreated and treated patients in cardiovascular prediction.

BACKGROUND:Whether central systolic blood pressure (cSBP) compared with brachial systolic blood pressure (bSBP) improves risk stratification remains debated. This study investigated whether cSBP is more closely associated with total and cardiovascular mortality than bSBP when recorded by 24-hour ambulatory BP monitoring with an arm cuff-based oscillometric monitor. METHODS:Consecutive patients referred for ambulatory BP monitoring and enrolled in the Shanghai Ruijin Ambulatory BP Monitoring Registry (2017-2023) were analyzed. bSBP and cSBP were recorded over 24 hours. cSBP was calibrated on brachial systolic and diastolic BP (cSBPc1) or on mean arterial pressure and brachial diastolic BP (cSBPc2). Total and cardiovascular mortality up to December 31, 2024, was assessed by record linkage with International Classification of Diseases, Tenth Revision, coded death certificates. Linear and nonlinear Cox proportional hazard regression was applied with age as the underlying time-scale and adjusted for established cardiovascular risk factors. RESULTS:Over 4.0 years of follow-up, 505 of 36 594 participants (52.8% women; median age, 53.4 years) died, 174 from cardiovascular disease. With multivariable adjustment applied, the nonlinear compared with linear Cox models provided a better model fit for both end points (P<0.001), irrespective of the period of the day and the calibration method of cSBP. Adding any 24-hour SBP to the base model increased the C statistics for total and cardiovascular mortality (0.003≤P≤0.06). Adding cSBPc1 or cSBPc2 to the base model extended by bSBP also increased the C statistics, but not by a statistically significant amount (0.054≤P≤0.22). CONCLUSIONS:cSBP compared with bSBP did not improve the associations with mortality. Measurement of the ambulatory bSBP is adequate for BP-based risk stratification.

ABSTRACT We performed a post hoc exploratory secondary analysis to investigate whether baseline circadian blood pressure (BP) pattern was associated with changes in serum uric acid (SUA) during 8‐week antihypertensive therapy. Of the 494 hypertensive patients who received amlodipine (5–10 mg) or nifedipine GITS (30–60 mg) for 8 weeks, 369 patients with available laboratory data and valid follow‐up ambulatory BP monitoring data were included in the present analysis, including 221 dippers (nocturnal systolic BP decline ≥ 10%) and 148 non‐dippers (nocturnal systolic BP decline < 10%). Analysis of covariance was used to estimate least square mean changes in SUA according to baseline dipping pattern. After 8‐week antihypertensive treatment, SUA decreased significantly in dippers (−12.4 ± 3.4 µmol/L, p = 0.0004) but not in non‐dippers (−3.3 ± 4.2 µmol/L, p = 0.44). In the repeated‐measures analysis, SUA levels decreased significantly over time ( p = 0.002), whereas no significant time‐by‐dipping interaction was observed ( p = 0.23). Baseline BP dipping pattern may be modestly associated with short‐term SUA changes during antihypertensive therapy. However, the absence of a significant time‐by‐dipping interaction suggests that these findings should be interpreted cautiously and require further confirmation.

Multiple articles focused on the central arterial systolic (SPTI) and diastolic (DPTI) pressure-time indexes and the subendocardial viability ratio (SEVR). However, whether these indexes contribute to risk stratification in the general population is unknown. SPTI, DPTI and SEVR were noninvasively measured by the SphygmoCor technology. Incidence rates and standardized (per 1-SD increment) multivariable-adjusted hazard ratios (HRs) for cardiovascular (primary) and cardiac endpoints and stroke were evaluated in the International Database of Central Arterial Properties for Risk Stratification (n = 5099). Model refinement was assessed by the area under the curve (AUC) and the integrated discrimination (IDI) and net reclassification (NRI) improvement. Over 4 years (median), 215 cardiovascular, 133 cardiac endpoints and 79 strokes occurred. For SPTI, fully adjusted HRs were 1.37 (95% CI: 1.18-1.59), 1.35 (1.11-1.64) and 1.33 (1.05-1.69) for the cardiovascular and cardiac endpoints and stroke. The corresponding HRs for DPTI were 1.49 (1.31-1.69), 1.23 (1.02-1.48) and 1.74 (1.46-2.07). For SEVR, none of the HRs reached significance. Analyses with these indexes categorized by quartiles were confirmatory. Analyses stratified by various risk factors did not reveal subgroup differences. For the cardiovascular endpoint, adding SPTI or DPTI to the base model improved the AUC, while adding SPTI or DPTI combined with mean arterial pressure, increased IDI by ~1.7% and NRI by ~17% (P < 0.001 for all). Whereas cardiovascular and cardiac endpoints and stroke were related with the non-invasively measured SPTI and DPTI, SEVR was not.

BACKGROUND:The ambulatory arterial stiffness index (AASI) is increasingly used in clinical research and practice. This individual-participant meta-analysis aims to consolidate the prognostic accuracy of AASI in the general population and to derive an end point-based AASI risk threshold. METHODS:In 12 558 individuals enrolled in 14 population studies (48.8% women; mean age, 59.3 years), AASI was derived by regressing 24-hour diastolic on systolic blood pressure (mm Hg/mm Hg). Using Cox regression, the risk-carrying AASI threshold was established by examining stepwise increasing AASI levels and by determining the AASI level, yielding a 10-year risk similar to an office systolic pressure of 140 mm Hg. RESULTS:Over 10.7 years (median), 3027 all-cause deaths and 2183 cardiovascular end points occurred. In all participants, multivariable-adjusted hazard ratios expressing the all-cause deaths and cardiovascular end point risk per 1-SD AASI increment were 1.08 (95% CI, 1.04-1.13) and 1.13 (95% CI, 1.07-1.18). In a randomly defined subset of 8189 individuals, the risk-carrying AASI thresholds converged to 0.50 with hazard ratios (≥0.50 versus <0.50) of 1.14 (95% CI, 1.04-1.26) for all-cause deaths and 1.13 (95% CI, 1.01-1.26) for cardiovascular end point. In the replication sample (n=4369), these hazard ratios were 1.13 (95% CI, 1.01-1.26) and 1.19 (95% CI, 1.04-1.35). AASI continuous or per threshold significantly improved model performance. Analyses of secondary end points and subgroups stratified by sex, age, hypertension status and treatment, history of cardiovascular disease, and nocturnal dipping were confirmatory. CONCLUSIONS:Over and beyond traditional risk factors, AASI improves risk stratification. Exceeding the risk-carrying 0.50 AASI threshold necessitates increased vigilance in managing risk factors before irreversible cardiovascular complications occur.

We investigated the blood pressure (BP) lowering efficacy of two dual antihypertensive therapies, the amlodipine/benazepril and benazepril/hydrochlorothiazide combinations, according to sodium sensitivity risk (SSR) as assessed by ambulatory BP monitoring (ABPM). In a multi-center, randomized, actively-controlled, parallel-group trial, patients with a clinic systolic/diastolic BP of 140 to 179/90 to 109 mmHg while on benazepril 10 mg daily monotherapy, received 24-week antihypertensive treatment with amlodipine/benazepril 5/10 mg (n = 213) or benazepril/hydrochlorothiazide 10/12.5 mg (n = 212). SSR was assessed with two 24-h ABPM parameters, BP dipper status at night and 24-h mean heart rate. The amlodipine/benazepril combination, compared with benazepril/hydrochlorothiazide combination, showed greater BP lowering effect in 304 patients with low/intermediate SSR, but smaller BP lowering effect in 121 patients with high SSR, with significant (P ≤ 0.046) interaction for 24-h, daytime and morning systolic BP. Indeed, in comparison with the benazepril/hydrochlorothiazide group, 24-h and daytime systolic BP reductions in the amlodipine/benazepril group were 4.19 and 5.17 mmHg, respectively, greater in patients with low/intermediate SSR, while morning systolic BP reductions was 10.8 mmHg smaller in patients with high SSR. Similar trends were observed for the other systolic BP measurements and diastolic BP measurements, although statistical significance was not attained (P ≥ 0.069). Sensitivity analysis in 367 patients with sustained hypertension was confirmatory. In conclusion, the antihypertensive treatment effect of the amlodipine/benazepril and benazepril/hydrochlorothiazide combinations was dependent on SSR as assessed by ABPM, with the former combination being more efficacious in patients with low/intermediate SSR, but less efficacious in patients with high SSR.

In the present analysis, we investigated the association between alcohol consumption and ambulatory blood pressure (BP) control in male patients after 8 weeks of antihypertensive therapy with two dihydropyridine calcium channel blockers. The study participants were hypertensive (clinic systolic/diastolic BP of 140-179/90-109 mmHg and 24-hour ambulatory systolic/diastolic BP ≥ 130/80 mmHg) patients enrolled in a randomized controlled trial and treated with amlodipine 5–10 mg or nifedipine gastrointestinal therapeutic system (GITS) 30–60 mg once daily. Alcohol consumption was classified as non-drinkers and drinkers. Non-dipping was defined as a BP drop from daytime to nighttime <10 Alcohol drinkers had higher nighttime systolic and diastolic blood pressure than non-drinkers at baseline. Clinic blood pressure-guided antihypertensive treatment was insufficient in changing the non-dipping to dipping pattern in alcohol drinkers with sustained clinic and ambulatory hypertension.

ABSTRACTPrognostic significance of the timing in the cardiac cycle of the first (TP1) and second (TP2) systolic peak of the central aortic pulse wave is ill‐defined. Incidence rates and standardized multivariable‐adjusted hazard ratios (HRs) of adverse health outcomes associated with TP1 and TP2, estimated by the SphygmoCor software, were assessed in the International Database of Central Arterial Properties for Risk Stratification (IDCARS) (n = 5529). Model refinement was assessed by the integrated discrimination (ID) and net reclassification (NR) improvement. Over 4.1 years (median), 201 participants died and 248 and 159 patients experienced cardiovascular or cardiac endpoints. Mean TP1 and TP2, standardized for cohort, sex, age, and heart rate, were 103 and 228 ms. Shorter TP1 and TP2 were associated with higher mortality and shorter TP1 with a higher risk of cardiovascular and cardiac endpoints (trend p ≤ 0.004). The HRs relating total mortality and cardiovascular endpoints to TP2 were 0.82 (95% confidence interval [CI]: 0.72–0.94) and 0.87 (0.77–0.98), respectively. The HR relating cardiac endpoints to TP1 was 0.81 (0.68–0.97). For total mortality and cardiovascular endpoints in relation to TP2, NRI was significant (p ≤ 0.010), but not for cardiac endpoints in relation to TP1. Integrated discrimination improvement (IDI) was not significant for any endpoint. The HRs relating total mortality to TP2 were smaller (p ≤ 0.026) in women than men (0.67 vs. 0.95) and in older (≥ 60 years) versus younger (< 60 years) participants (0.80 vs. 0.88). Our study adds to the evidence supporting risk stratification based on aortic pulse analysis by showing that TP2 and TP1 carry prognostic information.

BACKGROUND:This study assessed the presence of intracranial arterial stenosis (ICAS) in relation to home systolic blood pressure (SBP) and its variability (BPV). METHODS:In 1510 untreated patients, ICAS was assessed by transcranial Doppler ultrasonography. SBP and BPV were determined from individual home BP recordings over seven days with triplicate readings in the morning and evening. BP variability was expressed as standard deviation (SD), coefficient of variation (CV), variability independent of the mean (VIM), and average real variability (ARV). CV was SD divided by the mean, VIM was SD divided by the mean to the power x  and multiplied by the population mean to the power x, and ARV reflected the average absolute difference between consecutive BP readings. Associations with ICAS were assessed from nested multivariable logistic models. RESULTS:One hundred and fourteen participants (7.5%) had ICAS. Combining all BP readings, SBP, SD, CV, VIM, and ARV averaged (± between-patient SD) 130.1 ± 11.9 mm Hg, 8.36 ± 2.53 mm Hg, 6.42 ± 1.83%, 8.36 ± 2.38, and 6.41 ± 1.61 mm Hg, respectively. In multivariable-adjusted models, higher home SBP was independently associated with increased prevalence of ICAS. For morning measurements, all variability indices were significantly associated with ICAS, with odds ratios per 1-SD increase ranging from 1.33 to 1.34 (P ≤ 0.005), independent of SBP level. In contrast, associations based on evening variability were non-significant. Sex and anatomical ICAS location did not impact these results. CONCLUSIONS:The prevalence of ICAS was positively associated with SBP level. In addition to the SBP level, all four morning BPV indexes refined the assessment of ICAS prevalence.

Hypertension guidelines recommend multiple blood pressure measurements to minimize the potential initial alerting reactions. This study investigated the prognostic significance of this reaction in elderly individuals. The study subjects (aged ≥60 years) were recruited from the suburban Shanghai. Blood pressure was measured three times consecutively with a 60 s interval in the sitting position using an oscillometric device. An alerting reaction was defined as that the first blood pressure reading exceeded the average of the subsequent two readings. In the total of 4512 participants (44.7

AIMS:Thoracic aortic dissection (TAD) is a highly fatal disease lacking effective pharmacologic interventions in clinical practice. Emerging evidence indicates that the natriuretic peptide receptor C (NPR-C) plays a crucial role in the regulation of cardiovascular diseases. However, the precise involvement of NPR-C in TAD remains elusive. In this study, the role and molecular mechanisms of NPR-C in the pathogenesis of TAD were investigated. METHODS AND RESULTS:Through integrated analyses of human TAD transcriptome and single-cell sequencing data sets, we identified that NPR-C was downregulated in the aortas of acute TAD patients and in beta-aminopropionitrile (BAPN)-treated mice. Intriguingly, vascular smooth muscle cell (VSMC)-specific NPR-C knockout (NPR-CSMKO) mice, rather than endothelial cell-specific NPR-C knockout mice, developed TAD after treated with angiotensin II (Ang II) plus high salt diet (HSD), but not Ang II alone. Loss of NPR-C function promoted extracellular matrix degeneration, VSMCs apoptosis, and inflammation. RNA-sequencing analysis revealed that mitochondrial fatty acid oxidation (FAO) genes were significantly downregulated in the thoracic aortas of NPR-CSMKO mice treated with Ang II plus HSD. Notably, the expression of HADHB, a subunit of mitochondrial trifunctional protein (MTP) responsible for FAO, was obviously decreased in NPR-CSMKO mice treated with Ang II plus HSD. Mechanistically, knockdown of NPR-C activated ERK1/2 pathway, which decreased the expression and activity of peroxisome proliferator-activated receptor γ (PPARγ) and inhibited HADHB expression. Furthermore, NPR-C agonist, C-ANP4-23, mitigated the progression of TAD in BAPN-treated mice. Activation of MTP by spermidine (SPD) effectively prevented TAD formation in NPR-CSMKO mice treated with Ang II plus HSD. CONCLUSION:Our data highlight a critical role of HSD in triggering TAD and a previously unrecognized role of NPR-C that protects against TAD through regulating mitochondrial homeostasis. Therefore, NPR-C activation and SPD supplementation could be new prevention and treatment strategies for TAD.

Objective·To investigate the association of serum osteoglycin (OGN) levels with renal function and blood pressure in non-diabetic patients with hypertension.Methods·Hypertensive patients without a diagnosis of diabetes mellitus were recruited from the Hypertension Department of Ruijin Hospital, Shanghai Jiaotong University School of Medicine. A total of 36 renal dysfunction patients (renal dysfunction group) and 38 normal renal function patients (normal renal function group), matched for age, gender and clinic blood pressure, were included in this study. Serum OGN concentrations were measured by the enzyme-linked immunosorbent assay (ELISA). Estimated glomerular filtration rate (eGFR) was calculated from serum creatinine using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. The serum OGN levels were compared between the renal dysfunction group and the normal renal function group. The correlations of serum OGN level with eGFR and blood pressure were analyzed.Results·There was no significant statistical difference in serum OGN levels between the renal dysfunction group and the normal renal function group (P=0.708). Serum OGN levels were not significantly associated with eGFR (P=0.952). In the renal dysfunction group, mean arterial pressure, age and current smoking status were relevant factors of serum OGN levels (P<0.05). After adjustment for confounders, serum OGN levels were independently associated with clinic systolic and diastolic blood pressure, 24-hour ambulatory mean systolic and diastolic blood pressure in the renal dysfunction group (P<0.05), but not in the normal renal function group (P˃0.05).Conclusion·In non-diabetic patients with hypertension, serum OGN levels are not significantly associated with eGFR. In patients with renal dysfunction, higher serum OGN levels are independently associated with higher clinic systolic blood pressure, clinic diastolic blood pressure, 24-hour ambulatory mean systolic and diastolic blood pressure.

Abstract We investigated fasting hypertriglyceridemia as predictors of all‐cause, cardiovascular, and non‐cardiovascular mortality in an elderly male Chinese population, while accounting for various conventional cardiovascular risk factors. Our participants were elderly men recruited from residents living in a suburban town of Shanghai (≥60 years of age, n = 1583). Hypertriglyceridemia was defined as a fasting serum triglycerides concentration ≥1.70 mmol/L. Subgroup analyses were performed according to current smoking (yes vs. no), alcohol intake (yes vs. no), and the presence and absence of hypertension and hyperglycemia. During a median of 7.9 years follow‐up, all‐cause, cardiovascular, and non‐cardiovascular deaths occurred in 279, 112, and 167 participants, respectively. After adjustment for confounding factors, fasting hypertriglyceridemia was not significantly (p ≥ .33) associated with the risk of all‐cause, cardiovascular, and non‐cardiovascular mortality. However, there was significant (p = .03) interaction between hypertriglyceridemia and the presence and absence of hypertension in relation to all‐cause mortality. In normotensive, but not hypertensive individuals, hypertriglyceridemia was significantly associated with a higher risk of all‐cause mortality (hazard ratio 1.57, 95% confidence interval 1.06–2.31). In further non‐parametric analyses in normotensive individuals, the age‐standardized rate for all‐cause mortality increased from 18.9 in quartile 1 to 20.0, to 24.7, and to 39.9 per 1000 person‐years in quartiles 2, 3, and 4 of serum triglycerides concentration, respectively (ptrend = .0004). Similar results were observed for cardiovascular mortality. Our study in elderly male Chinese showed that fasting hypertriglyceridemia was associated with a higher risk of all‐cause and cardiovascular mortality in patients with normotension but not those with hypertension.

PURPOSE:The aim of this study was to investigate the association of macular microcirculation with renal function and the feasibility of using macular microcirculatory parameters to monitor renal function in Chinese non-diabetic patients with hypertension. METHODS:This case-control study included 62 non-diabetic patients with hypertension, including 31 with renal dysfunction (estimated glomerular filtration rate [eGFR] <90 mL/min/1.73 m2) and 31 with normal renal function (eGFR ≥90 mL/min/1.73 m2). Age, sex and clinic blood pressure were matched between groups. Macular microcirculatory parameters of 124 eyes of the 62 patients were evaluated by optical coherence tomography (OCT) and OCT angiography (OCTA). RESULTS:In comparison with the patients with normal renal function, patients with renal dysfunction had lower macular superficial parafovea vessel density (18.6 vs. 19.4%, P = 0.029), macular cube average thickness (273.0 vs. 280.2 µm, P = 0.003), and average ganglion cell layer and inner plexiform layer (GCL-IPL) thickness (79.5 vs. 82.8 µm, P = 0.006), but similar macular central fovea vessel density and central fovea thickness (P ≥ 0.54). After adjustment for confounders, eGFR was significantly associated with macular superficial parafovea vessel density, cube average thickness and GCL-IPL thickness (P < 0.02). In detecting renal dysfunction, areas under the curve were 0.61, 0.66 and 0.65 for macular superficial parafovea vessel density, cube average thickness and GCL-IPL thickness. CONCLUSION:In non-diabetic patients with hypertension, macular superficial parafovea vessel density, cube average thickness and GCL-IPL thickness were significantly worse in patients with renal dysfunction than those with normal renal function. Using macular parameters to monitor renal function is feasible.

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.

Objectives: We undertook time-stratified analyses of the National Health and Nutrition Examination Survey in the US to assess time trends (1999–2020) in the associations of blood lead (BL) with blood pressure, mortality, the BL-associated population attributable fraction (PAF). Methods: Vital status of participants, 20–79 years old at enrolment, was ascertained via the National Death Index. Regressions, mediation analyses and PAF were multivariable adjusted and standardized to 2020 US Census data. Results: In time-stratified analyses, BL decreased from 1.76 μg/dl in 1999–2004 to 0.93 μg/dl in 2017–2020, while the proportion of individuals with BL < 1 μg/dl increased from 19.2% to 63.0%. Total mortality was unrelated to BL (hazard ratio (HR) for a fourfold BL increment: 1.05 [95% confidence interval, CI: 0.93–1.17]). The HR for cardiovascular death was 1.44 (1.01–2.07) in the 1999–2000 cycle, but lost significance thereafter. BL was directly related to cardiovascular mortality, whereas the indirect BL pathway via BP was not significant. Low socioeconomic status (SES) was directly related to BL and cardiovascular mortality, but the indirect SES pathway via BL lost significance in 2007–2010. From 1999–2004 to 2017–2020, cardiovascular PAF decreased (P < 0.001) from 7.80% (0.17–14.4%) to 2.50% (0.05–4.68%) and number of lead-attributable cardiovascular deaths from 53 878 (1167–99 253) to 7539 (160–14 108). Conclusion: Due to implementation of strict environmental policies, lead exposure is no longer associated with total mortality, and the mildly increased cardiovascular mortality is not associated with blood lead via blood pressure in the United States.