Efficacy and safety of a single-pill versus free combination of perindopril/indapamide/amlodipine: a multicenter, randomized, double-blind study in Chinese patients with hypertension.

BACKGROUND: In China, the prevalence of hypertension is high and the use of combination antihypertensive therapy is low, which contributes to inadequate blood pressure (BP) control. The availability of simplified treatments combining complementary BP-lowering agents may help more patients achieve their goals. METHODS: This Phase III, multicenter, randomized, double-blind, noninferiority study included Chinese adults with mild-to-moderate hypertension. Following a 1-month run-in on perindopril/indapamide bi-therapy, patients with uncontrolled systolic/diastolic BP (≥140/90 mmHg) were randomized to perindopril 5 mg/indapamide 1.25 mg/amlodipine 5 mg (Per/Ind/Aml) single-pill combination (SPC) or perindopril 4 mg/indapamide 1.25 mg plus amlodipine 5 mg (Per/Ind + Aml) for 6 months. Uptitration was permitted from month 2 onwards. The primary efficacy objective was the noninferiority of Per/Ind/Aml in lowering office systolic BP at 2 months. The secondary objectives included the effectiveness of SPC on diastolic BP, uptitration efficacy, and office BP control (systolic/diastolic <140/90 mmHg). A subgroup of patients participated in 24-h ambulatory BP monitoring (ABPM). RESULTS: A total of 532 patients were randomized: Per/Ind/Aml (n = 262) and Per/Ind + Aml (n = 269). Overall, the mean (±SD) age was 55.7 ±â€Š8.8 years, 60.7% were male, and the mean office systolic/diastolic BP at baseline on Per/Ind was 150.4/97.2 mmHg. Systolic BP decreased in both groups at 2 months from baseline: -14.99 ±â€Š14.46 mmHg Per/Ind/Aml versus -14.49 ±â€Š12.87 mmHg Per/Ind +Aml. A predefined noninferiority margin of 4 mmHg was observed (P < 0.001). The effectiveness of the Per/Ind/Aml SPC was also demonstrated for all secondary endpoints. ABPM demonstrated sustained BP control over 24 h. Both treatments were well tolerated. CONCLUSIONS: Per/Ind/Aml is an effective substitute for Per/Ind + Aml, providing at least equivalent BP control over 24 h in a single pill, with comparable safety.

Poly-(ADP-ribose) polymerases inhibition by olaparib attenuates activities of the NLRP3 inflammasome and of NF-κB in THP-1 monocytes.

Poly-(ADP-ribose) polymerases (PARPs) are a protein family that make ADP-ribose modifications on target genes and proteins. PARP family members contribute to the pathogenesis of chronic inflammatory diseases, including atherosclerosis, in which monocytes/macrophages play important roles. PARP inhibition is protective against atherosclerosis. However, the mechanisms by which PARP inhibition exerts this beneficial effect are not well understood. Here we show that in THP-1 monocytes, inhibition of PARP by olaparib attenuated oxidized low-density lipoprotein (oxLDL)-induced protein expressions of nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing-3 (NLRP3) inflammasome components: NLRP3, apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC), and caspase-1. Consistent with this effect, olaparib decreased oxLDL-enhanced interleukin (IL)-1ß and IL-18 protein expression. Olaparib also decreased the oxLDL-mediated increase in mitochondrial reactive oxygen species. Similar to the effects of the NLRP3 inhibitor, MCC950, olaparib attenuated oxLDL-induced adhesion of monocytes to cultured human umbilical vein endothelial cells and reduced foam cell formation. Furthermore, olaparib attenuated the oxLDL-mediated activation of nuclear factor (NF)-κB through the oxLDL-mediated increase in IκBα phosphorylation and assembly of NF-κB subunits, demonstrated by co-immunoprecipitation of IκBα with RelA/p50 and RelB/p52 subunits. Moreover, PARP inhibition decreased oxLDL-mediated protein expression of a NF-κB target gene, VCAM1, encoding vascular cell adhesion molecule-1. This finding indicates an important role for NF-κB activity in PARP-mediated activation of the NLRP3 inflammasome. Thus, PARP inhibition by olaparib attenuates NF-κB and NLRP3 inflammasome activities, lessening monocyte cell adhesion and macrophage foam cell formation. These inhibitory effects of olaparib on NLRP3 activity potentially protect against atherosclerosis.

The association between arterial stiffness and cancer occurrence: Data from Kailuan cohort study.

Background: This study aimed to investigate whether increased arterial stiffness, measured by brachial-ankle pulse wave velocity (baPWV) is associated with cancer. Materials and methods: A total of 45,627 Chinese adults underwent a baPWV examination. The participants were followed up from 1st January 2012 to 31st December 2018. Cox proportional hazards model was used to assess the association between the baPWV values and cancer. Results: During a total follow-up duration of 172,775.69 person-years, there were 553 new cases of cancer. The subjects in the highest baPWV group showed an increased risk of cancer when compared with the lowest baPWV group as confirmed by multivariate-adjusted hazard ratios (HR = 1.51, 95% CI = 1.14∼2.00) in the entire cohort. Compared with participants in the lowest baPWV group, the HRs (95% CI) for digestive cancer in the second and third groups were 1.55 (1.00∼2.40) and 1.99 (1.19∼3.33), respectively. The Kaplan-Meier analysis demonstrated a significant increase in cancer in participants with a baPWV ≥ 18 m/s (P < 0.001). Compared with the lowest baPWV group, the highest baPWV group showed an increased risk of cancer in men (HR = 1.72, 95% CI = 1.22∼2.43) and those < 60 years (HR = 1.75, 95% CI = 1.20∼2.55), respectively. Conclusion: Increased arterial stiffness measured by baPWV is associated with cancer occurrence, especially digestive cancer occurrence. Clinical trial registration: ClinicalTrials.gov, identifier ChiCTR-TNRC-11001489.

Association of sodium intake with adverse left atrial function and left atrioventricular coupling in Chinese.

OBJECTIVES: High sodium intake is strongly associated with hypertension and obesity. This study aims to investigate the relationship between 24-h urinary sodium (a surrogate measure of sodium intake), ambulatory blood pressure parameters, left atrial function, and left atrioventricular coupling. Further, we intend to examine whether blood pressure and BMI might be mediators of the relationship between 24-h urinary sodium and subclinical cardiac function. METHODS: Our study had 398 participants, all of whom were subjected to 24-h urine collection, 24-h ambulatory blood pressure measurement, and cardiac magnetic resonance imaging. RESULTS: The average age of the participants was 55.70 ±â€Š11.30 years old. The mean urinary sodium of the participants was 172.01 ±â€Š80.24 mmol/24 h. After adjusting for age, sex, history of diabetes, smoking status, alcohol consumption, and use of diuretics, 24-h urinary sodium was correlated with multiple ambulatory blood pressure parameters, BMI, left atrial function, and the left atrioventricular coupling index (LACI) (P < 0.05). Mediation analysis showed that BMI explained 16% of the indirect effect of 24-h urinary sodium and left atrial function and 30% of the indirect effect of LACI. Independent of the mediator, 24-h urinary sodium had a significant direct effect on left atrial function and left atrioventricular coupling. CONCLUSIONS: Higher 24-h urinary sodium was associated with a greater BMI as well as poor left atrial function and left atrioventricular coupling, and the BMI mediated the relationship between 24-h urinary sodium and subclinical left cardiac function. Furthermore, and more importantly, 24-h urinary sodium may have directly affected the left atrial function and left atrioventricular coupling independent of intermediary factors.

Efficacy of angiotensin receptor neprilysin inhibitor in Asian patients with refractory hypertension.

Sacubitril/valsartan, simultaneously inhibits neprilysin and angiotensin II receptor, showed an effect in reducing blood pressure (BP). The authors aimed to study whether it can be used as an antihypertensive agent in patients with refractory hypertension who have already been treated. A total of 66 Chinese patients with refractory hypertension were enrolled. Patients received sacubitril/valsartan  200 instead of angiotensin II receptor blocker or angiotensin converting enzyme inhibitor while other agents continued. If BP was uncontrolled after 4 weeks, sacubitril/valsartan was increased to 400 mg. The BP reduction was evaluated by office BP and ambulatory BP monitoring after 8-week treatment. The baseline office BP and mean arterial pressure (MAP) were 150.0/95.0 mmHg and 113.3 mmHg. BP and MAP reduced to 130.6/83.2 mmHg and 99.0 mmHg at week 8. Office BP and MAP reductions were 19.4/11.8 mmHg and 14.3 mmHg at endpoint (all p < .001). The 24-h, daytime and nighttime ambulatory BP were 146.2/89.1, 148.1/90.3, and 137.5/83.7 mmHg, respectively at baseline, and BP reduced to 129.6/79.8, 130.6/81.1, and 121.7/75.8 mmHg, respectively at week 8. The 24-h, daytime and nighttime ambulatory BP reductions were 16.6/9.3, 17.5/9.2, and 15.8/7.9 mmHg, respectively at endpoint (all p < .001). Sacubitril/valsartan significantly reduced office and ambulatory BP in refractory hypertension patients. Our study provided new evidence for sacubitril/valsartan in refractory hypertension.

Osteopontin N-Terminal Function in an Abdominal Aortic Aneurysm From Apolipoprotein E-Deficient Mice.

The cleavage of osteopontin (OPN) by thrombin results in an N-terminal fragment (OPN-N), which exposes a cryptic integrin-binding motif that promotes the adherence of cells, and plays a proinflammatory role. However, the effect of OPN-N on abdominal aortic aneurysm (AAA) remains unknown. The aim of this study was to investigate the expression of OPN-N in aortic tissue samples obtained from patients, who underwent acute aortic dissection (AD), and normal aorta, effect of OPN-N on angiotensin (Ang) II-induced AAA in mice, and relationship between OPN-N and pyroptosis-related inflammatory factors in vitro. Hematoxylin and eosin staining was conducted to detect histological changes. Next, we detected the expression of the OPN-N protein. Additionally, ApoE-/- mice were divided into four groups: control, control + M5Ab (to block the OPN-N function in mice), Ang II, and Ang II + M5Ab. All mice were euthanized after a 28-day infusion and whole aortas, including thoracic and abdominal aortas, were collected for morphological and histological analysis of the AAA. The OPN-N protein expression was higher in patients with AD than in normal individuals, while histological changes in the aortas of Ang II mice were suppressed in Ang II + M5Ab mice. The expression of OPN-N, NOD-, LRR-, and pyrin domain-containing protein 3, pro-Caspase-1, ASC, Gasdermin-d, interleukin (IL)-18, IL-1ß, matrix metalloproteinase (MMP) 2, and MMP9 was lower in the Ang II + M5Ab group than in the Ang II group. The gene expression of monocyte chemoattractant protein-1, IL-6, and tumor necrosis factor-α was suppressed in the aortic tissues of the Ang II + M5Ab group compared with the Ang II group. Moreover, the expression of α-smooth muscle actin was lower in the Ang II group than in the Ang II + M5Ab group. In vitro results showed that the increase in the expression of pyroptosis-related inflammatory factors induced by OPN was mediated through the nuclear factor (NF)-κB pathway. In conclusion, OPN-N promotes AAA by increasing the expression of pyroptosis-related inflammatory factors through the NF-κB pathway, inflammation, and extracellular matrix degradation. These results highlight the potential of OPN-N as a new therapeutic target to prevent AAA expansion.

Rutaecarpine Inhibits Doxorubicin-Induced Oxidative Stress and Apoptosis by Activating AKT Signaling Pathway.

Patients with cancer who receive doxorubicin (DOX) treatment can experience cardiac dysfunction, which can finally develop into heart failure. Oxidative stress is considered the most important mechanism for DOX-mediated cardiotoxicity. Rutaecarpine (Rut), a quinazolinocarboline alkaloid extracted from Evodia rutaecarpa was shown to have a protective effect on cardiac disease. The purpose of this study is to investigate the role of Rut in DOX-induced cardiotoxicity and explore the underlying mechanism. Intravenous injection of DOX (5 mg/kg, once a week) in mice for 4 weeks was used to establish the cardiotoxic model. Echocardiography and pathological staining analysis were used to detect the changes in structure and function in the heart. Western blot and real-time PCR analysis were used to detect the molecular changes. In this study, we found that DOX time-dependently decreased cardiac function with few systemic side effects. Rut inhibited DOX-induced cardiac fibrosis, reduction in heart size, and decrease in heart function. DOX-induced reduction in superoxide dismutase (SOD) and glutathione (GSH), enhancement of malondialdehyde (MDA) was inhibited by Rut administration. Meanwhile, Rut inhibited DOX-induced apoptosis in the heart. Importantly, we further found that Rut activated AKT or nuclear factor erythroid 2-related factor 2 (Nrf-2) which further upregulated the antioxidant enzymes such as heme oxygenase-1 (HO-1) and GSH cysteine ligase modulatory subunit (GCLM) expression. AKT inhibitor (AKTi) partially inhibited Nrf-2, HO-1, and GCLM expression and abolished the protective role of Rut in DOX-induced cardiotoxicity. In conclusion, this study identified Rut as a potential therapeutic agent for treating DOX-induced cardiotoxicity by activating AKT.

Relationship between Insulin Secretion and Arterial Stiffness in Essential Hypertension.

The study aims to explore the relationship between plasma insulin secretion and arterial stiffness in nondiabetic essential hypertensive patients. A total of 730 nondiabetic essential hypertensive patients registered between January 2016 and October 2020 were enrolled. A two-hour oral glucose tolerance test (OGTT) was performed to detect the levels of C-peptide and blood glucose at 0 hours and 2 hours, as well as the difference between C-peptide (Δ C-peptide) and blood glucose (Δ blood glucose) over the same period. Patients were divided into two groups: the normal glucose tolerance (NGT) group (n = 322) and the impaired glucose tolerance (IGT) group (n = 408). A multiple linear regression analysis was used to evaluate the association between brachial-ankle pulse wave velocity (baPWV) and the other factors. 0 h C-peptide, 2 h C-peptide, and Δ C-peptide were found to be higher in the IGT group. baPWV was positively linear correlated with 2 h C-peptide (r = 0.086, p=0.020) and Δ C-peptide (r = 0.115, p=0.002). baPWV remained independently associated with 0 h C-peptide, 2 h C-peptide, and Δ C-peptide, after adjusting by age, gender, smoking, body mass index (BMI), high-density lipoprotein (HDL), cholesterol, systolic blood pressure (SBP), and triglycerides (TG). Our data shows that higher endogenous insulin secretion might play an important role in the progression of arterial stiffness in nondiabetic essential hypertensive patients.

l-arginine alleviates doxorubicin-induced endothelium-dependent dysfunction by promoting nitric oxide generation and inhibiting apoptosis.

BACKGROUND/AIMS: Patients with doxorubicin (Dox) treatment have a high risk of developing vascular toxicity with an unknown mechanism. l-arginine is a substrate for nitric oxide (NO). The decreased level of arginine-NO metabolite in Dox-treated cancer patients was associated with increased level of vascular damage, which promoted us to investigate the mechanism of Dox-induced vascular dysfunction and verify whether l-arginine supplement could alleviate this vasculotoxic effect. METHOD: Within a mouse model of Dox injection (5 mg/kg i.p., 2 or 4 weeks), we measured vascular relaxation, blood pressure, vascular NO generation, apoptosis, and oxidative stress. We tested the efficacy of l-arginine (1.5 mg/g/day, 4 weeks) on Dox-induced vascular relaxation, blood pressure, vascular NO generation, apoptosis, as well as oxidative stress. RESULTS: Dox induced endothelium-dependent vascular dysfunction, which was associated with increased reactive oxidative stress (ROS) production and reduced NO generation in the vessel. ROS was required for Dox-induced apoptosis of both smooth muscle cells and endothelial cells. Dox treatment in mice increased blood pressure, but had no effect on vascular inflammation and fibrosis. L-aringine restored Dox-induced vascular dysfunction via enhancing vascular NO production and alleviating ROS-mediated apoptosis. CONCLUSION: We for the first time demonstrated l-arginine was effectively in suppressing Dox-induced vascular dysfunction, by attenuating vascular NO release and apoptosis. Our results provide a therapeutic target or a circulating marker for assessing vascular dysfunction which response to Dox treatment, and advance our understanding of the mechanisms of Dox-induced vascular dysfunction.

Protective effect of thymoquinone improves cardiovascular function, and attenuates oxidative stress, inflammation and apoptosis by mediating the PI3K/Akt pathway in diabetic rats.

Thymoquinone is the main active monomer extracted from black cumin and has anti­inflammatory, antioxidant and anti­apoptotic functions. However, the protective effects of thymoquinone on cardiovascular function in diabetes remain to be fully elucidated. The present study aimed to investigate the molecular mechanisms underling the beneficial effects of thymoquinone on the cardiovascular function in streptozotocin­induced diabetes mellitus (DM) rats. Supplement thymoquinone may recover the insulin levels and body weight, inhibit blood glucose levels and reduce the heart rate in DM­induced rats. The results indicated that the heart, liver and lung to body weight ratios, in addition to the blood pressure levels, were similar for each experimental group. Treatment with thymoquinone significantly reduced oxidative stress damage, inhibited the increased endothelial nitric oxide synthase protein expression and suppressed the elevation of cyclooxygenase­2 levels in DM­induced rats. In addition, thymoquinone significantly suppressed the promotion of tumor necrosis factor­α and interleukin­6 levels in the DM­induced rats. Furthermore, administration of thymoquinone significantly reduced caspase­3 activity and the promotion of phosphorylated­protein kinase B (Akt) protein expression levels in DM­induced rats. These results suggest that the protective effect of thymoquinone improves cardiovascular function and attenuates oxidative stress, inflammation and apoptosis by mediating the phosphatidylinositol 3­kinase/Akt pathway in DM­induced rats.

Soluble Fas ligand and atherosclerosis in hypertensive patients.

BACKGROUND: The Fas-Fas ligand (FasL) system is involved in apoptosis in many types of cells. Recently, the expression of FasL on endothelial cells was reported. FasL is cleaved by a metalloproteinase and released in serum as soluble FasL (sFasL). Vasoactive substances, including metalloproteinase, are modulated by endothelial dysfunction. Advanced atherosclerosis and impaired endothelial function are seen in hypertensive patients. The inflammatory response has an important role in the development of atherosclerosis, whereas C-reactive protein (CRP) is associated with the presence and severity of atherosclerosis. OBJECTIVE: To measure the intima-media thickness of the common carotid artery and evaluate the relationship between atherosclerosis and serum sFasL concentrations in hypertensive patients. PATIENTS AND MAIN OUTCOME MEASURES: Forty-seven patients with hypertension participated in the study. The intima-media thickness of the common carotid artery was evaluated by ultrasound imaging. Serum concentrations of sFasL were measured by enzyme-linked immunosorbent assay. RESULTS: Intima-media thickness correlated positively with age (r = 0.362, P = 0.012) and sFasL concentrations (r =0.332, P = 0.022), and negatively with creatinine clearance (r = -0.399, P = 0.0055). A general linear model analysis with atherosclerotic risk factors and sFasL revealed that age, sFasL, high-density lipoprotein-cholesterol and systolic blood pressure were significantly associated with intima-media thickness. Furthermore, we demonstrated that serum sFasL is directly associated with CRP concentration (r = 0.316, P = 0.030). CONCLUSIONS: These results indicated that serum sFasL concentration is associated with atherosclerosis and inflammatory disease, in patients with hypertension.