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Background: Effectiveness of a non-physician community health-care provider-led intensive blood pressure intervention on cardiovascular disease has not been established. We aimed to test the effectiveness of such an intervention compared with usual care on risk of cardiovascular disease and all-cause death among individuals with hypertension., Methods: In this open-label, blinded-endpoint, cluster-randomised trial, we recruited individuals aged at least 40 years with an untreated systolic blood pressure of at least 140 mm Hg or a diastolic blood pressure of at least 90 mm Hg (≥130 mm Hg and ≥80 mm Hg for those at high risk for cardiovascular disease or if currently taking antihypertensive medication). We randomly assigned (1:1) 326 villages to a non-physician community health-care provider-led intervention or usual care, stratified by provinces, counties, and townships. In the intervention group, trained non-physician community health-care providers initiated and titrated antihypertensive medications according to a simple stepped-care protocol to achieve a systolic blood pressure goal of less than 130 mm Hg and diastolic blood pressure goal of less than 80 mm Hg with supervision from primary care physicians. They also delivered discounted or free antihypertensive medications and health coaching for patients. The primary effectiveness outcome was a composite outcome of myocardial infarction, stroke, heart failure requiring hospitalisation, and cardiovascular disease death during the 36-month follow-up in the study participants. Safety was assessed every 6 months. This trial is registered with ClinicalTrials.gov, NCT03527719., Findings: Between May 8 and Nov 28, 2018, we enrolled 163 villages per group with 33 995 participants. Over 36 months, the net group difference in systolic blood pressure reduction was -23·1 mm Hg (95% CI -24·4 to -21·9; p<0·0001) and in diastolic blood pressure reduction, it was -9·9 mm Hg (-10·6 to -9·3; p<0·0001). Fewer patients in the intervention group than the usual care group had a primary outcome (1·62% vs 2·40% per year; hazard ratio [HR] 0·67, 95% CI 0·61-0·73; p<0·0001). Secondary outcomes were also reduced in the intervention group: myocardial infarction (HR 0·77, 95% CI 0·60-0·98; p=0·037), stroke (0·66, 0·60-0·73; p<0·0001), heart failure (0·58, 0·42-0·81; p=0·0016), cardiovascular disease death (0·70, 0·58-0·83; p<0·0001), and all-cause death (0·85, 0·76-0·95; p=0·0037). The risk reduction of the primary outcome was consistent across subgroups of age, sex, education, antihypertensive medication use, and baseline cardiovascular disease risk. Hypotension was higher in the intervention than in the usual care group (1·75% vs 0·89%; p<0·0001)., Interpretation: The non-physician community health-care provider-led intensive blood pressure intervention is effective in reducing cardiovascular disease and death., Funding: The Ministry of Science and Technology of China and the Science and Technology Program of Liaoning Province, China., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: The prevalence of uncontrolled hypertension is high and increasing in low-income and middle-income countries. We tested the effectiveness of a multifaceted intervention for blood pressure control in rural China led by village doctors (community health workers on the front line of primary health care)., Methods: In this open, cluster randomised trial (China Rural Hypertension Control Project), 326 villages that had a regular village doctor and participated in the China New Rural Cooperative Medical Scheme were randomly assigned (1:1) to either village doctor-led multifaceted intervention or enhanced usual care (control), with stratification by provinces, counties, and townships. We recruited individuals aged 40 years or older with an untreated blood pressure of 140/90 mm Hg or higher (≥130/80 mm Hg among those with a history of cardiovascular disease, diabetes, or chronic kidney disease) or a treated blood pressure of 130/80 mm Hg or higher. In the intervention group, trained village doctors initiated and titrated antihypertensive medications according to a standard protocol with supervision from primary care physicians. Village doctors also conducted health coaching on home blood pressure monitoring, lifestyle changes, and medication adherence. The primary outcome (reported here) was the proportion of patients with a blood pressure of less than 130/80 mm Hg at 18 months. The analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, NCT03527719, and is ongoing., Findings: Between May 8 and November 28, 2018, we enrolled 33 995 individuals from 163 intervention and 163 control villages. At 18 months, 8865 (57·0%) of 15 414 patients in the intervention group and 2895 (19·9%) of 14 500 patients in the control group had a blood pressure of less than 130/80 mm Hg, with a group difference of 37·0% (95% CI 34·9 to 39·1%; p<0·0001). Mean systolic blood pressure decreased by -26·3 mm Hg (95% CI -27·1 to -25·4) from baseline to 18 months in the intervention group and by -11·8 mm Hg (-12·6 to -11·0) in the control group, with a group difference of -14·5 mm Hg (95% CI -15·7 to -13·3 mm Hg; p<0·0001). Mean diastolic blood pressure decreased by -14·6 mm Hg (-15·1 to -14·2) from baseline to 18 months in the intervention group and by -7·5 mm Hg (-7·9 to -7·2) in the control group, with a group difference of -7·1 mm Hg (-7·7 to -6·5 mm Hg; p<0·0001). No treatment-related serious adverse events were reported in either group., Interpretation: Compared with enhanced usual care, village doctor-led intervention resulted in statistically significant improvements in blood pressure control among rural residents in China. This feasible, effective, and sustainable implementation strategy could be scaled up in rural China and other low-income and middle-income countries for hypertension control., Funding: Ministry of Science and Technology of China., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Arterial hypertension represents the most frequent cardiovascular risk factor that is associated with cardiac remodeling. Hypertensive heart disease was defined by the presence of left ventricular hypertrophy (LVH) and diastolic dysfunction, and it has been diagnosed by echocardiography in everyday clinical practice. Interstitial myocardial fibrosis is the underlying cause of hypertension-induced cardiac remodeling, and it could not be visualized with different echocardiographic methods. Cardiac magnetic resonance (CMR) and its methods such as late gadolinium enhancement, and T1 mapping provides qualitative and quantitative assessment of interstitial myocardial fibrosis in hypertensive patients. Furthermore, CMR can provide differentiation of LVH between hypertensive patients and cardiomyopathies (hypertrophic or Fabry disease). Timely diagnosis of cardiac impairment and early treatment is essential because regression of LVH could be achieved with adequate treatment. Diffuse cardiac fibrosis in hypertensive patients might be an underlying mechanism that explains the increased cardiovascular morbidity and mortality in this population. Future longitudinal investigations are necessary to determine causal relationship between diffuse fibrosis and cardiovascular outcome in these patients. The aim of this review is to summarize the current knowledge regarding CMR techniques and their potential usage in patients with hypertensive heart disease., (© 2020. Springer Science+Business Media, LLC, part of Springer Nature.)

Hypertension is characterized by resistance artery remodeling driven by oxidative stress and fibrosis. We previously showed that an activin A antagonist, follistatin, inhibited renal oxidative stress and fibrosis in a model of hypertensive chronic kidney disease. Here, we investigate the effects of follistatin on blood pressure and vascular structure and function in models of essential and secondary hypertension. 5/6 nephrectomised mice, a model of secondary hypertension, were treated with either exogenous follistatin or with a follistatin miRNA inhibitor to increase endogenous follistatin for 9 weeks. Blood pressure in mice was measured by tail cuff. Spontaneously hypertensive rats, a model of essential hypertension, were treated with follistatin for 8 weeks. Wistar Kyoto (WKY) rats were used as the normotensive control. Blood pressure in rats was measured by radiotelemetry. Mouse superior mesenteric arteries and rat first branch mesenteric arteries were isolated for structural and functional analyses. In both models, follistatin significantly lowered blood pressure and improved vascular structure, decreasing medial thickness and collagen content. Follistatin also reduced agonist-induced maximum contraction and improved endothelium-dependent relaxation. Increased vessel oxidative stress was attenuated by follistatin in both models. In ex vivo WKY vessels, activin A increased oxidative stress, augmented constriction, and decreased endothelium-dependent relaxation. Inhibition of oxidative stress restored vessel relaxation. This study demonstrates that follistatin lowers blood pressure and improves vascular structure and function in models of essential and secondary hypertension. Effects were likely mediated through its inhibition of activin A and oxidative stress. These data suggest a potential therapeutic role for follistatin as a novel antihypertensive agent. Follistatin, through antagonization of activin A, inhibits oxidative stress and improves vascular structure and function in resistance arteries from models of essential and secondary HTN. FST decreases collagen content and vascular ROS. Functionally, FST improves endothelium-dependent relaxation and decreases maximal vasoconstriction. Improved resistance artery structure and function are correlated with a decrease in BP in both models., (© 2024. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

Background: Autosomal dominant hypertension with brachydactyly type E syndrome caused by pathogenic variants in the PDE3A gene was first reported in 2015. To date, there are only a few reports of this kind of syndrome. Other patients still lack a genetic diagnosis., Case Presentation: Whole-exome sequencing was performed in an 18-year-old female proband with a clinical diagnosis of hypertension with brachydactyly syndrome. Quantitative real-time PCR was used to identify pathogenic copy number variations (CNVs). After bioinformatics analysis and healthy control database filtering, we revealed a heterozygous missense PDE3A variant (c.1346G > A, p.Gly449Asp). The variant was absent in the ExAC database and located in a highly evolutionarily conserved cluster of reported PDE3A pathogenic variants. Importantly, this variant was predicted to affect protein function by both SIFT (score = 0) and PolyPhen-2 (score = 1). After Sanger sequencing, the variant was determined to be absent in the healthy parents of the proband as well as 800 ethnically and geographically matched healthy controls., Conclusion: We present a report linking a de novo PDE3A variant to autosomal dominant hypertension with brachydactyly type E syndrome.

Background There has been significant controversy regarding the effects of pre-hospitalization use of renin-angiotensin system (RAS) inhibitors on the prognosis of hypertensive COVID-19 patients. Methods and Results We retrospectively assessed 2,297 hospitalized COVID-19 patients at Tongji Hospital in Wuhan, China, from January 10 th to March 30 th , 2020; and identified 1,182 patients with known hypertension on pre-hospitalization therapy. We compared the baseline characteristics and in-hospital mortality between hypertensive patients taking RAS inhibitors (N=355) versus non-RAS inhibitors (N=827). Of the 1,182 hypertensive patients (median age 68 years, 49.1% male), 12/355 (3.4%) patients died in the RAS inhibitors group vs. 95/827 (11.5%) patients in the non-RAS inhibitors group (p<0.0001). Adjusted hazard ratio for mortality was 0.28 (95% CI 0.15-0.52, p<0.0001) at 45 days in the RAS inhibitors group compared with non-RAS inhibitors group. Similar findings were observed when patients taking angiotensin receptor blockers (N=289) or angiotensin converting enzyme inhibitors (N=66) were separately compared with non-RAS inhibitors group. The RAS inhibitors group compared with non-RAS inhibitors group had lower levels of C-reactive protein (median 13.5 vs. 24.4 pg/mL; p=0.007) and interleukin-6 (median 6.0 vs. 8.5 pg/mL; p=0.026) on admission. The protective effect of RAS inhibitors on mortality was confirmed in a meta-analysis of published data when our data were added to previous studies (odd ratio 0.44, 95% CI 0.29-0.65, p<0.0001). Conclusions In a large single center retrospective analysis we observed a protective effect of pre-hospitalization use of RAS inhibitors on mortality in hypertensive COVID-19 patients; which might be associated with reduced inflammatory response.

In the initial stage, left ventricular hypertrophy (LVH) is adaptive, but in time, it transforms to maladaptive LVH which is specific for the development of various phenotypes that cause heart failure, initially with preserved, but later with reduced left ventricular ejection fraction. Pathophysiological mechanisms, which are characteristic for remodeling procedure, are numerous and extremely complex, and should be subjected to further research with the aim of making a comprehensive overview of hypertensive heart disease (HHD) and discovering new options for preventing and treating HHD. The contemporary methods, such as cardiac magnetic resonance (CMR) and computed tomography (CT) provide very accurate morphological and functional information on HHD. The objective of this review article is to summarize the available scientific information in terms of prevalence, pathophysiology, diagnostics, prevention, contemporary therapeutic options, as well as to present potential therapeutic solutions based on the research of pathological mechanisms which are at the core of HHD., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Hypertension control is suboptimal globally. Implementing evidence-based, simple, standardized treatment protocols (STPs) has been instrumental in effectively and efficiently improving treatment and control of hypertension. We aimed to identify, characterize, and critically appraise hypertension STPs., Methods: We defined STP as a series of steps for the pharmacological treatment of primary hypertension, with information on target population, BP threshold for treatment initiation, target BP, specific drugs/classes/doses, and follow-up frequency. STPs for adult patients were identified from the websites of relevant health organizations, Google search, and through expert consultations (until July 2023). STPs for secondary, gestational, or malignant hypertension or those that were templates/samples were excluded. Included STPs were critically appraised using HEARTS in the Americas Checklist for hypertension management in primary care and compared with the 2021 WHO hypertension management guideline recommendations., Results: Fifty STPs were identified. All STPs had a stepwise treatment approach, involved guideline-recommended first-line drugs, and 98% consisted of at least four steps. Majority (54%) recommended monotherapy with calcium channel blockers as first-line treatment. Only 44% STPs recommended treatment initiation with combination therapy, and 16% recommended single-pill combinations. Most (62%) had dose-intensification as the second step. Most (74%) STPs did not provide complete dosing information. Only one STP mentioned a target time for achieving BP control. On average, STPs scored a performance of 68% on the HEARTS Checklist., Conclusion: Several STPs are available globally; however, most of them have enormous scope for improvement through interventions aimed at alignment with the latest evidence-based guidelines and multistakeholder engagement., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Human cytochrome P450 (CYP) enzymes have a wide range of endogenous substrates and play a crucial role in cardiovascular physiology as well as in metabolic processes, so the issue of cytochrome P450 genes investigation has received considerable critical attention in the prevention of cardiovascular diseases (CVDs)., Aim: Comprehensive assessment of relationship between CYP2C19*2, CYP2C19*3 polymorphisms and CVD risk factors in gas industry workers undergoing periodic medical examination (PME)., Materials and Methods: The study included 193 gas industry workers aged 30-55 years without acute diseases as well as exacerbations of chronic diseases, diabetes mellitus, and CVD history. CYP2C19 (rs4244285 and rs4986893) genotyping and analysis of the relationship between CYP2C19*2 and CYP2C19*3 and CVD risk factors were performed., Results: The CYP2C19*2 (A) and CYP2C19*3 (A) loss-of-function alleles frequencies were 20% and 2%, respectively. The frequency of high-normal blood pressure (BP) (130-139 and/or 85-89 mm Hg) detection was higher in the CYP2C19*2 (A) subgroup compared with wild-type GG allele carriers (26.7% vs. 5.2%, p = 0.03) in individuals without arterial hypertension (AH) and BP ≥ 140 and/or 90 mm Hg on PME. The median systolic BP levels were 5 mm Hg higher in CYP2C19*2 (A) group than in CYP2C19*2 (GG) group (125 vs. 120 mm Hg, p = 0.01). There was a similar trend for diastolic BP (85 vs. 80 mmHg, p = 0.08). CYP2C19*2 (A) was associated with higher mean levels of both systolic and diastolic BP (p = 0.015 and p = 0.044, respectively) in patients with AH. CYP2C19*2 was not associated with the other CVD risk factors analyzed., Conclusion: The association of CYP2C19*2 with BP level suggests a possible role of this factor in AH development, which requires further research., (© 2023. Italian Society of Hypertension.)

Objective: To investigate the effect of consistently blood pressure (BP) control status after discharge on adverse clinical outcomes among ischemic stroke (IS) patients., Methods: Three thousand, four hundred and six acute IS patients were included and followed up at 3 months, 12 months, and 24 months after stroke. Study outcomes were defined as death, vascular events and composite of death or vascular events. Cox proportional hazard models were used to estimate hazard ratios (HR) and 95% confident interval (CI) of death and the composite outcome of death or vascular events associated with BP control and antihypertensive medication use., Results: The multivariable adjusted HRs were 0.22 [95% confidence interval (CI): 0.09-0.57] for death and 0.60 (95% CI: 0.39-0.97) for the composite outcome of death or vascular events among participants with consistently controlled BP compared with those with consistently uncontrolled BP. The participants with both consistently controlled BP and regular use of antihypertensive medication had the lowest risks of death [hazard ratio (HR): 0.18, 95% CI: 0.04-0.75] and composite outcome of death or vascular events (HR: 0.54, 95% CI: 0.29-0.98) in comparison with those with both uncontrolled BP and irregular use of antihypertensive medication., Discussion: Continuous BP control and regular use of antihypertensive medications after discharge can decrease the risks of death and composite outcome of death or vascular events among IS patients, suggesting the importance of continuous BP control and regular use of antihypertensive medications after discharge for improving prognosis of IS., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: Diet pattern (DP) is a key modifiable and cost-effective factor in hypertension (HTN) management. The current study aimed to identify and compare the hypertension-protective DPs among Chinese adults., Methods: 52,648 participants aged over 18 years were included from China Nutrition and Health Surveillance (CNHS) 2015-2017. Reduced rank regression (RRR) and partial least square regression (PLS) was applied to identify the DPs. Multivariable-adjusted logistic regression was used to assess the association between the DPs and HTN., Results: DPs derived by RRR and PLS were both featured by higher consumption of fresh vegetables and fruits, mushrooms and edible fungi, seaweeds, soybeans and related products, mixed legumes, dairy products, fresh eggs, and lower of refined grain consumption. Compared to the lowest quintile, participants in the highest quintile had lower odds of HTN (RRR-DP: OR = 0.77, 95% CI = 0.72-0.83; PLS-DP: OR = 0.76, 95% CI = 0.71-0.82; all p < 0.0001). Simplified DP scores were observed the same protective tendencies (Simplified RRR-DP: OR = 0.81, 95% CI = 0.75-0.87; Simplified PLS-DP: OR = 0.79, 95% CI = 0.74-0.85; all p < 0.0001) and showed effective extrapolation in subgroups defined by gender, age, location, lifestyle, and different metabolic conditions., Conclusions: The identified DPs had high conformity with East Asian dietary habits, and significantly negative associations with HTN among Chinese adults. The simplified DP technique also indicated the potential for improving the extrapolation of the results of DP analysis related to HTN., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background: Excessive reactive oxygen species generated in mitochondria has been implicated as a causal event in hypertensive cardiomyopathy. Multiple recent studies suggest that microRNAs (miRNAs) are able to translocate to mitochondria to modulate mitochondrial activities, but the medical significance of such a new miRNA function has remained unclear. Here, we characterized spontaneous hypertensive rats (SHRs) in comparison with Wistar rats, finding that micro RNA-21 (miR-21) was dramatically induced in SHRs relative to Wistar rats. We designed a series of experiments to determine whether miR-21 is involved in regulating reactive oxygen species generation in mitochondria, and if so, how induced miR-21 may either contribute to hypertensive cardiomyopathy or represent a compensatory response., Methods: Western blotting was used to compare the expression of key nuclear genome (nDNA)-encoded and mitochondrial genome (mtDNA)-encoded genes involved in reactive oxygen species production in SHRs and Wistar rats. Bioinformatics was used to predict miRNA targets followed by biochemical validation using quantitative real-time polymerase chain reaction and Ago2 immunoprecipitation. The direct role of miRNA in mitochondria was determined by GW182 dependence, which is required for miRNA to function in the cytoplasm, but not in mitochondria. Recombinant adeno-associated virus (type 9) was used to deliver miRNA mimic to rats via tail vein, and blood pressure was monitored with a photoelectric tail-cuff system. Cardiac structure and functions were assessed by echocardiography and catheter manometer system., Results: We observed a marked reduction of mtDNA-encoded cytochrome b (mt-Cytb) in the heart of SHRs. Downregulation of mt-Cytb by small interfering RNA in mitochondria recapitulates some key disease features, including elevated reactive oxygen species production. Computational prediction coupled with biochemical analysis revealed that miR-21 directly targeted mt-Cytb to positively modulate mt-Cytb translation in mitochondria. Circulating miR-21 levels in hypertensive patients were significantly higher than those in controls, showing a positive correlation between miR-21 expression and blood pressure. Remarkably, recombinant adeno-associated virus-mediated delivery of miR-21 was sufficient to reduce blood pressure and attenuate cardiac hypertrophy in SHRs., Conclusions: Our findings reveal a positive function of miR-21 in mitochondrial translation, which is sufficient to reduce blood pressure and alleviate cardiac hypertrophy in SHRs. This observation indicates that induced miR-21 is part of the compensatory program and suggests a novel theoretical ground for developing miRNA-based therapeutics against hypertension., (© 2016 American Heart Association, Inc.)

Considering that calcium/calmodulin-dependent kinase 4 (CAMK4) plays a pivotal role in blood pressure regulation, we investigated the association between a CAMK4 polymorphism (rs10491334) and hypertension in the Han, Kazak, and Uygur ethnic groups. We studied 1224 patients with hypertension and 967 normotensive controls classified into three ethnic groups (Han, Kazak, and Uygur). The rs10491334 polymorphism was genotyped using a TaqMan® 5'-nuclease assay. In the Uygur group, the T-allele frequency in patients with hypertension was twice that of the controls (12.5 vs 6.38%), and T-allele carriers had a significantly increased risk of hypertension compared with non-carriers (odds ratio = 2.200; 95% confidence interval = 1.473-3.285, P < 0.001). However, no significant correlation was found in the Han and Kazak groups. The T-allele of rs10491334 in CAMK4 was associated with hypertension in the Uygur group.

Context and Objective: Dimethylarginine dimethylaminohydrolase enzymes (DDAH), which are encoded by the genes DDAH1 and DDAH2, play a fundamental role in maintaining endothelial function. We conducted a case-control study on a Chinese population that included three ethnic groups (Han, Kazakh and Uygur), to systemically investigate associations between variations in the genes DDAH1 and DDAH2 and hypertension., Design and Setting: Experimental study at the Department of Internal Medicine and Genetic Diagnosis, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology., Methods: This case-control study included 1,224 patients with hypertension and 967 healthy unrelated individuals as controls. DDAH1 -396 4N (GCGT) del>ins, rs3087894, rs805304 and rs9267551 were genotyped using the TaqMan 5' nuclease assay., Results: The G/C genotype of rs3087894 in DDAH1 was a risk factor for hypertension in the Kazakh group in the co-dominant model (G/C versus G/G) (OR 1.39; 95% CI: 1.02-1.88; P < 0.05), with the same result in the dominant model (G/C + C/C versus G/G) (OR 1.38; 95% CI: 1.03-1.84; P < 0.05). In contrast, the C/C genotype of rs3087894 seemed to be a protective factor against hypertension in the Uygur group in the recessive model (C/C versus G/G + G/C) (OR 0.62; 95% CI: 0.39- 0.97; P < 0.05). Similar findings for rs3087894 were also observed after adjusting the variable for the age covariate., Conclusion: Our results indicated that the C-allele of rs3087894 in DDAH1 was a risk factor for hypertension in the Kazakh group but a protective factor in the Uygur group.

Background and Purpose: Thiazide diuretics (TD), including thiazide-type (chlorothiazide and hydrochlorothiazide) and thiazide-like diuretics (indapamide and chlorthalidone), have been used for the treatment of hypertension for more than 5 decades. This meta-analysis aimed to evaluate whether TD, including thiazide-type and thiazide-like diuretics have additional cardioprotective effects., Experimental Approach: We performed a pooled study of 19 randomized clinical trials (RCTs). PubMed and EMBASE databases were searched for RCTs assessing TD treatment in patients with hypertension., Key Results: Nineteen RCTs involving 112,113 patients (56,802 in TD; 55,311 in control) were included. The incidence ratio of cardiac events (CVs) was 34.3 vs. 37.8 per 1,000 patient-years in patients randomized to TD and controls, respectively. TD treatment was associated with reductions in the risks of CVs (odds ratio (OR): 0.86, P = 0.007) and heart failure (OR: 0.62, P < 0.001), but not different in stroke (OR: 0.92, P = 0.438) or CHD (OR: 0.95, P = 0.378) between diuretics and controls. Further analysis showed that the observed benefits were mainly confined to thiazide-like diuretic therapy rather than thiazide-type diuretics with a significant reduction in the risk of CVs (OR: 0.78, P < 0.001), heart failure (OR: 0.57, P < 0.001) and stroke (OR: 0.82, P = 0.016)., Conclusions and Implications: This study suggests that use of TD in hypertensive patients results in a reduction in the risk of CVs. Moreover, thiazide-like diuretics have greater protective effect against CVs than thiazide-type diuretics, especially on heart failure, suggesting that preferential use of thiazide-like diuretics over thiazide-type diuretics may result in greater cardiovascular benefits in hypertensive patients., (© American Journal of Hypertension, Ltd 2015. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: To systemically investigate the association between the polymorphism (rs3118869) in cathepsin Lenzyme gene with hypertension in three ethnic groups (Han, Kazak and Uygur) in China., Study Design: Case-control study., Place and Duration of Study: Department of Cardiology, The First Affiliated Hospital, Shihezi Medical College, Shihezi University and Department of Internal Medicine and Genetic Diagnosis Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, from January 2013 to May 2014., Methodology: This case-control study included 1224 patients (422 Uygur, 425 Kazak and 377 Han individuals) with hypertension and 967 healthy unrelated individuals (339 Uygur, 337 Kazak and 291 Han individuals) as controls. The participants came from three ethnic groups (Han, Kazak and Uygur) which were recruited from Xinjiang Province of China. The polymorphism (rs3118869) of the human cathepsin Lgene was genotyped using the TaqMan 5' nuclease assay. Binary logistic regression was built to determine the association of polymorphism with hypertension., Results: The genotype distribution of polymorphism was not significantly different in three ethnic groups. The rs3118869 polymorphism was significantly associated with Essential Hypertension (EH) in co-dominant model (A/C vs. C/C) in total people (OR = 0.697, 95% CI = 0.520 -0.932, p = 0.015), the same result was obtained in recessive model (C/C + A/C vs. A/A) in total people (OR = 0.689, 95% CI = 0.522 -0.910, p = 0.009). Similar finding of rs3118869 in recessive model (C/C + A/C vs. A/A) was also observed after adjusting the variable to the covariates age (OR = 0.629, 95% CI = 0.464 0853, p = 0.003)., Conclusion: The study results indicate the A-allele of rs3118869 is a protective factor in hypertension.

Heart failure with preserved ejection fraction (HFpEF) represents a highly heterogeneous clinical syndrome affected in its development and progression by many comorbidities. The left ventricular diastolic dysfunction may be a manifestation of various combinations of cardiovascular, metabolic, pulmonary, renal, and geriatric conditions. Thus, in addition to treatment with sodium-glucose cotransporter 2 inhibitors in all patients, the most effective method of improving clinical outcomes may be therapy tailored to each patient's clinical profile. To better outline a phenotype-based approach for the treatment of HFpEF, in this joint position paper, the Heart Failure Association of the European Society of Cardiology, the European Heart Rhythm Association and the European Hypertension Society, have developed an algorithm to identify the most common HFpEF phenotypes and identify the evidence-based treatment strategy for each, while taking into account the complexities of multiple comorbidities and polypharmacy., (© 2023 European Society of Cardiology.)

Objective: To explore the distribution laws of TCM syndrome types and to analyze the distribution of dynamic blood pressure curve, atherosclerosis, and age in senile hypertension patients., Methods: Totally 1 131 senile hypertension patients were recruited from 7 provinces and municipal cities. Features of TCM syndromes, classification and distribution curves, and syndrome distribution laws were observed. The distribution curves of dynamic blood pressure, carotid atherosclerosis, and age were compared in each TCM syndrome types., Results: There were four main syndrome types in 736 cases (56.15%), i.e., excessive accumulation of phlegm-dampness syndrome (210 cases, 16.02%), yin deficiency and hyperactivity of yang syndrome (177 cases, 13.50%), Gan-Shen yin deficiency syndrome (79 cases, 6.03%), and deficiency of qi and yin syndrome (252 cases, 19.22%). Besides, there were two more sub-types, i.e., collateral obstruction by blood stasis syndrome and collateral obstruction by phlegm and stasis. Circadian blood pressure monitor was completed in 211 cases. Of them, abnormal circadian blood pressure occurred in 152 cases (accounting for 72. 38%); yin deficiency and hyperactivity of yang syndrome, excessive accumulation of phlegm-dampness syndrome, deficiency of qi and yin syndrome plus collateral obstruction by blood stasis syndrome were most often seen. Color ultrasound of carotid artery was performed in 660 patients of main syndromes. The incidence was quite higher in those of excessive accumulation of phlegm-dampness syndrome (182 cases, 27. 58%), deficiency of qi and yin syndrome plus collateral obstruction by blood stasis syndrome or collateral obstruction by phlegm and stasis (322 cases, 48.79%). Yin deficiency and hyperactivity of yang syndrome was dominant in patients 60 -79 years old, while deficiency of qi and yin syndrome and Gan-Shen yin deficiency syndrome were dominant in patients older than 80 years., Conclusions: Excessive accumulation of phlegm-dampness syndrome, yin deficiency and hyperactivity of yang syndrome, Gan-Shen yin deficiency syndrome, and deficiency of qi and yin syndrome were main syndrome types in senile hypertension patients. There was statistical difference in the distribution curves of blood pressure, atherosclerosis, and age of various TCM syndrome types.

Objectives: Tissue kallikrein (TK) has been shown to provide cardiovascular and cerebrovascular protective effects in animal models. The aim of this study was to investigate the relationship of plasma TK levels with the presence and severity of coronary artery disease (CAD) in the Chinese., Methods: The study involved 898 consecutive CAD patients and 905 ethnically and geographically matched controls. CAD was angiographically confirmed in all the patients, and the severity of CAD was expressed by the number of affected vessel and coronary artery stenosis scores. Plasma TK levels were measured using an enzyme-linked immunosorbent assay., Results: Plasma TK levels were significantly higher in CAD patients than controls (0.347±.082 vs. 0.256±0.087 mg/L, P<0.001), and elevated plasma TK levels were directly associated with a higher risk of CAD (OR = 3.49, 95% CI 2.90-4.19). One-way ANOVA and multivariable stepwise linear regression analysis demonstrated that TK levels were negatively associated with the severity of CAD according to vessel scores (P<0.001) and stenosis scores (r = -0.211, p<0.001)., Conclusions: Our findings suggest that higher levels of TK in plasma are associated with the presence of CAD and are a predictor of mild coronary arteriosclerosis.

Background: Rho-kinase (ROCK) has been shown to play an important role in cardiovascular disease such as coronary artery disease (CAD) and hypertension. Recently, common variants of ROCK2 have been reported to influence blood pressure, but the relationship between common ROCK2 variants and cardiovascular disease has not been extensively studied in the Chinese population., Methods: To derive a more precise estimation of their relationship, we screened for the common variants by direct sequencing of all exons of ROCK2, and then we performed genetic association analyses in a CAD case-control study, including a total of 1344 cases and 1267 ethnically and geographically matched controls., Results: Unconditional logistic regression showed that no significant association between common variants in the coding region of ROCK2 and CAD was observed in our study (for rs978906, OR = 0.92, 95% CI 0.72-1.20 and P = 0.63; for rs2230774, OR = 0.90, 95% CI 0.70-1.16 and P = 0.47; for rs56304104, OR = 0.97, 95% CI 0.70-1.31 and P = 0.83; respectively)., Conclusions: The relationship between the ROCK2 polymorphisms and cardiovascular disease risk cannot be entirely discounted and warrants further evaluation in a large population.

Objective: To investigate the association between rs751141 gene polymorphisms in EPHX2 gene and essential hypertension in Kazak and Han in Xinjiang., Methods: A total of 267 essential hypertensive patients in Kazaks, 368 essential hypertensive patients in Hans, 284 normotensive controls in Kazaks and 348 normotensive controls in Hans were enrolled in this study. TaqMan assay was used to detect the rs751141 G/A gene polymorphisms of EPHX2 gene., Results: The rs751141 G/A genotype frequencies for GA + AA genotypes was 40.2 percent in essential hypertensive subjects and 52.0 percent in control subjects in Hans, respectively. The genotype frequencies were significant difference between the two groups in Hans in Xinjiang (P < 0.01). The rs751141G/A gene polymorphism had no significant difference between essential hypertensive patients and normotensive controls in Kazaks in Xinjiang (P > 0.05)., Conclusion: The essential hypertension in Kazaks in Xinjiang is not associated with rs751141G/A gene polymorphism of EPHX2 gene, but the essential hypertension in Hans in Xinjiang is associated with rs751141G/A allele gene polymorphism of EPHX2 gene. A type of rs751141 allele gene polymorphism may be the independent protective factor of essential hypertension in Hans in Xinjiang.

C-reactive protein (CRP) has been shown to function as an inflammatory factor to induce endothelial dysfunction and hypertension in rats. The anti-inflammatory effects of statins suggest that they may attenuate CRP-induced endothelial dysfunction and hypertension in Sprague-Dawley rats. Male Sprague-Dawley rats were injected with an adeno-associated virus (AAV) to induce overexpression of human CRP (AAV-hCRP) or green fluorescent protein (GFP) control (AAV-GFP). At 2 months after injection, rats were administered rosuvastatin by daily oral gavage (10 mg kg(-1)) for 2 additional months. Rosuvastatin administration attenuated the increased blood pressure and loss of vascular endothelial nitric oxide synthase expression in AAV-hCRP-treated rats, and N-nitro-L-arginine methyl ester blocked its hypotensive effect. Rosuvastatin also activated phosphoinositide 3-kinases/Akt, and inhibited Rho kinase activity in aorta. Rosuvastatin reduced the production of reactive oxygen species through downregulation of nicotinamide adenine dinucleotide phosphate oxidase subunits, p22 phox and gp91 phox, and upregulation of superoxide dismutase 1 expression. Rosuvastatin attenuated the increase in blood pressure in AAV-hCRP-treated rats through endothelial protection and antioxidant effects. Our data reveals a novel mechanism through which statins may lower blood pressure.

Cytochrome P450 (P450)-derived epoxyeicosatrienoic acids (EETs) exert well recognized vasodilatory, diuretic, and tubular fluid-electrolyte transport actions that are predictive of a hypotensive effect. The study sought to determine the improvement of hypertension and cardiac function by overexpressing P450 epoxygenases in vivo. Long-term expression of CYP102 F87V or CYP2J2 in spontaneously hypertensive rats (SHR) was mediated by using a type 8 recombinant adeno-associated virus (rAAV8) vector. Hemodynamics was measured by a Millar Instruments, Inc. (Houston, TX) microtransducer catheter, and atrial natriuretic peptide (ANP) mRNA levels were tested by real-time polymerase chain reaction. Results showed that urinary excretion of 14,15-EET was increased at 2 and 6 months after injection with rAAV-CYP102 F87V and rAAV-CYP2J2 compared with controls (p < 0.05). During the course of the 6-month study, systolic blood pressure significantly decreased in P450 epoxygenase-treated rats, but the CYP2J2-specific inhibitor C26 blocked rAAV-CYP2J2-induced hypotension and the increase in EET production. Cardiac output was improved by P450 epoxygenase expression at 6 months (p < 0.05). Furthermore, cardiac collagen content was reduced in P450 epoxygenase-treated rats. ANP mRNA levels were up-regulated 6- to 14-fold in the myocardium, and ANP expression was significantly increased in both myocardium and plasma in P450 epoxygenase-treated rats. However, epidermal growth factor (EGF) receptor antagonist 4-(3'-chloroanilino)-6,7-dimethoxy-quinazoline (AG-1478) significantly attenuated the increase in the EET-induced expression of ANP in vitro. These data indicate that overexpression of P450 epoxygenases attenuates the development of hypertension and improves cardiac function in SHR, and that these effects may be mediated, at least in part, by ANP via activating EGF receptor.

Aim: Overexpression of human tissue kallikrein (HK), mediated by recombinant adeno-associated virus (rAAV), decreased blood pressure in spontaneous hypertensive rats (SHRs) and reduced injury to the heart, aorta and kidney. In this study, we used both an in vivo animal model and in vitro cell culture system to investigate whether rAAV-mediated HK gene therapy protects against organ damage by inhibiting cell apoptosis., Methods: rAAV encoding HK (rAAV-HK) or LacZ (rAAV-lacZ) were delivered as a control to spontaneously hypertensive rats (SHRs) and cultured human embryonic kidney (HEK) 293 cells., Results: Treatment with rAAV-HK decreased cell apoptosis in the target organs of SHRs and also inhibited lipopolysaccharide (LPS)-induced HEK 293 apoptosis. The rAAV-HK delivery system also increased the levels of apoptosis-inhibiting proteins bcl-2 and bcl-x(L), and decreased the level of Bax and the activity of caspase 3, two promoters of apoptosis. In addition to its role in the inhibition of apoptosis, rAAV-HK also activated the cell survival and proliferation signaling pathways ERK1/2 and PI3K/AKT., Conclusion: rAAV-mediated HK gene delivery has multiple therapeutic possibilities for treating hypertension, not only by decreasing blood pressure, but also by directly inhibiting end-organ damage.

Background: Prospective studies have shown that C-reactive protein (CRP) is a predictor of hypertension. Because of confounding variables, a causal linkage between CRP and hypertension has not been clearly shown. We investigated whether high circulating concentrations of human CRP can induce hypertension in rats., Methods: We administered a single intravenous injection of adeno-associated virus-green fluorescent protein (AAV-GFP) or AAV-hCRP and measured blood pressure. Using ELISA, we measured serum hCRP, serum endothelin 1 (ET-1), and urine cGMP, and we measured serum nitric oxide (NO) using the Griess method. We recorded heart rate, maximum pressure, arterial elastance, mean aortic pressure, cardiac output, and maximum rate of rise in left ventricular pressure (dP/dt max)., Results: A single injection of AAV-hCRP resulted in efficient and sustained hCRP expression and led to increased blood pressure 2 months after gene transfer that persisted for another 2 months. This effect was associated with decreased NO production, as demonstrated by decreased serum NO concentration and urinary cGMP excretion, and impairment of endothelial-dependent vascular relaxation. CRP transduction also increased expression of angiotensin type 1 receptor, ET-1, and endothelin type A receptor, decreased expression of angiotensin type 2 receptor and endothelial NO synthase in thoracic aortas, and increased arterial stiffness. Ex vivo studies indicated a similar detrimental effect of CRP that was reversed by the NO donor., Conclusion: AAV vector-mediated CRP expression resulted in hypertension mediated through reduced NO production and subsequent alteration in ET-1 and renin-angiotensin system activation. Impaired arterial elasticity may also contribute to CRP-induced hypertension. These results support a causal role for CRP in the pathogenesis of hypertension.

Endothelial dysfunction and decreased production of nitric oxide (NO) by endothelial NO synthase (eNOS) are implicated in the pathogenesis of hypertension and insulin resistance. Because the potential influence of increased eNOS expression/activity on these parameters is unclear, the present study examined the effects of eNOS gene therapy on insulin resistance and blood pressure alterations in a fructose-induced hypertension model in rats. As predicted, 2 weeks of fructose consumption in the drinking water resulted in elevated systolic blood pressure and insulin resistance. These and other physiologic alterations were reversed within 2 weeks after a single intravenous injection of a vector containing the human eNOS cDNA (pcDNA3.1-eNOS), whereas injection of an empty vector (pcDNA3.1) was without effect. In support of the beneficial effects of pcDNA3.1-eNOS treatment being because of enhanced eNOS expression and activity, increased eNOS protein levels were documented in aorta, liver, kidney, and heart of fructose-treated rats injected with pcDNA3.1-eNOS, and corresponding elevations in nitrite/nitrate and cGMP concentrations were observed in urine. Furthermore, pcDNA3.1-eNOS treatment prevented fructose-induced decreases in expression levels of insulin receptor substrate-1, the p110 catalytic subunit of phosphatidylinositol 3-kinase, phosphorylated Akt, and phosphorylated AMP-activated protein kinases in liver, aorta, and skeletal muscle. The results of this study cumulatively indicate that gene therapy with human eNOS decreased fructose-induced hypertension and insulin resistance in rats and suggest potential signaling pathways that mediate these effects. These data highlight the potential utility of eNOS gene therapy in the treatment of hypertension and insulin resistance.

Aim: To investigate the effects of the expression of human kallikrein (HK) on basal level blood pressure and high-salt diet-induced hypertension., Methods: We delivered the recombinant adeno-associated viral (rAAV)-mediated HK (rAAV- HK) gene and rAAV-LacZ (as the control) to normal, adult Sprague-Dawley rats. The animals were administered a normal diet in the first 4 weeks, followed by a high-salt diet. The expression of HK in the rats was assessed by ELISA and RT- PCR. Blood pressure and Na+ and K+ urinary excretion were monitored., Results: Under the normal diet, no obvious changes in blood pressure and Na+ and K+ urinary excretion were observed. When the high-salt diet was administered, systolic blood pressure in the control animals receiving rAAV-LacZ increased from 122.3+/-1.13 mmHg to a stable 142.4+/-1.77 mmHg 8 weeks after the high-salt diet. In contrast, there was no significant increase in the blood pressure in the rAAV-HKtreated group, in which the blood pressure remained at 121.9+/-1.73 mmHg. In the rAAV-HK-treated group, Na+ and K+ urinary excretion were higher compared to those of the control group. The morphological analysis showed that HK delivery remarkably protected against renal damage induced by a high-salt intake., Conclusion: Our study indicates that rAAV-mediated human tissue kallikrein gene delivery is a potentially safe method for the long-term treatment of hypertension. More importantly, it could be applied in the salt-sensitive population to prevent the occurrence of hypertension.

Aim: The overexpression of the human tissue kallikrein (HK) gene can reduce blood pressure and ameliorate the secondary syndromes associated with hypertension in animal models. The current study was designed to investigate hypotensive effect of intramuscular delivery of HK gene., Methods: We generated an recombinant adeno-associated virus (rAAV) vector expressing human tissue kallikrein under the control of a cytomegalovirus promoter and administered the rAAV-HK vector to a spontaneously hypertensive rat model at a dose of 1 x 10(10) virons/rat through intramuscular injection., Results: A persistent, high-level expression of HK post-gene delivery was confirmed by ELISA. The systolic blood pressure in the rats receiving rAAV-LacZ and saline increased from 171.3 mmHg to 182.3 mmHg 28 weeks' post injection. In contrast, the delivery of the HK gene by AAV vectors attenuated the increase of the systolic blood pressure in the treated group. The systolic blood pressure was only slightly lowered (from a level of 174 mmHg to 170.5 mmHg) post-vector administration. The difference in blood pressure between the treated group and the control groups is statistically significant at 12.6 mmHg. The hypotensive effect of rAAV-HK persisted until the end of the testing period. In addition, a significant amelioration of cardiovascular hypertrophy, renal injury, and collagen depositions in the rAAV-HK-treated animals were also observed., Conclusion: All the effects are comparable with those of intravenous delivery. Therefore, the intramuscular administration of rAAV-HK may be used in gene therapy for hypertension.

Aim: The renin-angiotensin system plays a crucial role in the development and establishment of hypertension, and the pharmacological blockade of the system results in a reduction in blood pressure. In the present study, we investigated whether the effects of a novel, double-stranded, recombinant adeno-associated virus vector (rAAV)-mediated antisense angiotensin II receptor 1 (AT1R) gene efficiently prevents the development of hypertension induced by a high-salt diet in adult, male Sprague-Dawley (SD) rats., Methods: A rAAV was prepared with a cassette containing a cytomegalovirus promoter and partial cDNA (660 base pairs) for the AT1R inserted in the antisense direction (rAAV-AT1-AS). A single tail vein injection of the rAAV-AT1-AS or rAAV-GFP (green fluorescent protein, a reporter gene) was performed in adult, male SD rats. Two weeks after injection, the animals were fed a diet containing 8% NaCl, and the systolic blood pressure was measured weekly using the tail-cuff method for 12 weeks., Results: The high-salt diet induced a significant rise in systolic blood pressure in the rAAV-GFP-treated animals; however, the rAAV-AT1-AS treatment attenuated the rise in blood pressure (142.7+/-4.5 mmHg vs 117+/-3.8 mmHg, P<0.01), and the hypotensive effect was maintained until the experiments ended at 12 weeks. In the rAAV-GFP-treated animals AT1 was overexpressed in various tissues, especially in the aorta and kidney at mRNA levels; in contrast, rAAV-AT1-AS treatment markedly attenuated AT1 expression. Furthermore, rAAV-AT1-AS treatment prevented target organ damages from hypertension, including cardiac dysfunction and renal injury compared to the rAAV-GFP group., Conclusion: These results suggest that rAAVmediated anti-AT1 delivery attenuates the development of hypertension and protects against renal injury and cardiac remodeling.

Arachidonic acid cytochrome P-450 (CYP) hydroxylase 4A isoforms, including 4A1, 4A2, 4A3 and 4A8 in the rat kidney, catalyze arachidonic acid to produce 19/20-Hydroxyeicosatetraenoic acids (20-HETE), a biologically active metabolite, which plays an important role in the regulation of blood pressure. However, controversial results have been reported regarding the exact role of 20-HETE on blood pressure. In the present study, we used recombinant adeno-associated viral vector (rAAV) to deliver CYP 4A1 cDNA and antisense 4A1 cDNA into Sprague-Dawley (SD) rats and spontaneously hypertensive rats (SHR), respectively, to investigate the effects of long-term modifications of blood pressure and the potential for gene therapy of hypertension. The mean systolic pressure increased by 14.2+/-2.5 mm Hg in rAAV.4A1-treated SD rats and decreased by 13.7+/-2.2 mm Hg in rAAV.anti4A1-treated SHR rats 5 weeks after the injection compared with controls and these changes in blood pressure were maintained until the experiments ended at 24 weeks. In 4A1 treated animals CYP4A was overexpressed in various tissues, but preferentially in the kidney at both mRNA and protein levels. In anti-4A1-treated SHR, CYP4A mRNA in various tissues was probed, especially in kidneys, but 4A1 protein expression was almost completely inhibited. These results suggest that arachidonic acid CYP hydroxylases contribute not only to the maintenance of normal blood pressure but also to the development of hypertension. rAAV-mediated anti4A administration strategy has the potential to be used as targeted gene therapy in human hypertension by blocking expression of CYP 4A in kidneys.

Adrenomedullin (AM) is a hypotensive peptide that functions as an important regulator in the cardiovascular and renal systems. The current study explored the potential therapeutic effects of delivering the human AM cDNA via a novel double-stranded adeno-associated virus vector (dsAAV) on hypertension and related complications in spontaneously hypertensive rats (SHR). A single dose of dsAAV-AM vector administered by tail vein injection into adult SHR resulted in significant reduction of systolic blood pressure at 2 weeks after gene delivery. This effect was observed through the entire duration of the experiment period (up to 16 weeks). Administration of dsAAV-AM also resulted in a decrease in total urine microalbumin content. Left ventricle and cardiomyocyte hypertrophy, fibrosis in the heart, glomerular sclerosis, and tubular injuries in the kidney were significantly reduced. Moreover, deterioration of hemodynamic variables was prevented in treated rats, as compared with the control groups. We conclude that AAV-mediated AM delivery can render a longterm and stable reduction of hypertension and protect against renal injury and cardiac remodeling in the spontaneously hypertensive rat model. Further preclinical studies are warranted for the development of a gene therapy strategy for human hypertension.

Gene therapy of hypertension requires long-term expression of a therapeutic gene to achieve stable reduction of blood pressure. Human tissue kallikrein (HK) cleaves kininogen to produce a potent vasoactive peptide kinin, which plays an important role in the regulation of the cardiovascular and renal functions. In the present study, we have delivered human kallikrein cDNA with an rAAV vector to explore the potential therapeutic effects of kallikrein on hypertension and related secondary complications. A single tail vein injection of the rAAV-HK vector into the adult spontaneously hypertensive rats resulted in a significant reduction (12.0+/-2.55 mmHg, P<0.05, n=6, ANOVA) of the systolic blood pressure from 2 weeks after vector injection, when compared with the control rAAV-lacZ vector-injected rats. Weekly blood pressure monitoring showed stable hypertension-reduction effect throughout the course of the 20-week experiments. In addition, total urine microalbumin contents decreased as a result of rAAV-HK treatment. Histological analysis of various tissues showed remarkable amelioration of cardiovascular hypertrophy, renal injury and collagen depositions in the rAAV-treated group. Finally, persistent expression of the transgene product HK was confirmed by the enzyme-linked immunosorbent assay and reverse transcription-polymerase chain reaction. We conclude that rAAV-mediated HK delivery rendered a long-term and stable reduction of hypertension and protected against renal injury, cardiac remodeling in the spontaneously hypertensive rat model. Further studies are warranted for the development of a gene therapy strategy for human hypertension.

This study investigates gene therapy with human tissue kallikrein as a treatment for fructose-induced hypertension in rats. Hypertension was induced by addition of 10% fructose to drinking water. Fructose-fed rats also had increased serum insulin and triglycerides, decreased urine osmolarity, increased urine volume and endothelin-1, and increased aortic endothelin-1, endothelin-A receptor, and angiotensin II receptor type 1 mRNA levels. Fructose-induced hypertensive and control rats were injected intravenously with a construct containing the human tissue kallikrein cDNA. Two weeks after injection of hypertensive rats, systolic blood pressure and serum insulin levels normalized, urine osmolarity increased, urine endothelin-1 levels decreased, and aortic endothelin-1, endothelin-A receptor, and angiotensin II receptor type 1 mRNA levels decreased. In contrast, injection of the human tissue kallikrein cDNA had minimal effect on blood pressure or insulin levels in control rats. These results suggest that gene therapy with human tissue kallikrein may have potential as a treatment for hypertension and associated insulin resistance. Moreover, our data suggest that the beneficial effects of human tissue kallikrein on these parameters are associated with changes in endothelin-1, endothelin-A receptor, and angiotensin II receptor type 1 expression.

Aim: To investigate the relationship of kidney-specific expression of cytochrome P-450 (CYP) 4A1 and the blood pressure., Methods: The specific sense and antisense CYP4A1 cDNA was administered respectively with the help of eukaryotic expression vector pcDNA3.1 to the Sprague-Dawley (SD) rats via sublingual vein (2 mg/kg). The systolic blood pressure of rats was assessed by the tail- cuff method, and the relative tissue expression of CYP4A1 was analyzed by Western blot and Northern blot at RNA and protein levels in the brain, heart, lung, liver, and kidney of control, sense, and anti-sense CYP4A1 cDNA-treated rats., Results: Two weeks after the injection of the sense and antisense CYP4A1 cDNA recombinants respectively, the mean systolic pressure of the transgenic rats increased by 1.8 kPa +/- 0.3 kPa (13.2 mmHg +/- 2.5 mmHg) or decreased by 1.7 kPa +/- 0.3 kPa (13.0 mmHg +/- 2.2 mmHg) compared with control. At the levels of transcription and translation, the Northern and Western blots all demonstrated that CYP4A1 preferentially overexpressed in the kidney., Conclusion: The administration of sense and antisense CYP4A1 cDNA induced hypertension and hypotension, respectively, which indicated that renal arachidonate hydroxylase contributed to the formation of hypertension and maintenance of blood pressure in normotensive rats.

Background: Angiotensin II can impair endothelial function, which is mediated by the angiotensin II type 1 receptor subtype., Objective: To test the hypothesis that treatment with the angiotensin II type 1 receptor antagonist losartan would restore the normal dilation of the left main coronary artery to the cold pressor test in patients with essential hypertension, as assessed by echocardiography., Patients and Methods: The study population included 24 patients with mild to moderate essential hypertension and 24 matched, healthy subjects. The cold pressor test-induced and nitroglycerin-induced changes in the left main coronary artery diameter were measured by echocardiography at the end of the washout period and after 12 weeks of losartan administration., Results: The percentage change in the left main coronary artery diameter induced by the cold pressor test in patients with hypertension (-4.3 8.7%) was significantly lower than that in control subjects (10.5 3.9%, P<0.0001). The percentage change in the left main coronary artery diameter induced by the cold pressor test in patients with essential hypertension after losartan treatment (13.7 8.0%) was significantly higher than that before losartan treatment (-4.3 8.7%, P<0.0001). The percentage change in the left main coronary artery diameter induced by the cold pressor test after losartan treatment was not significantly different between the 14 patients with hypertension who had satisfactory control of blood pressure (14.1 8.8%) and the 10 patients with hypertension who did not have satisfactory control of blood pressure (13.1 7.0, P=0.8). Losartan treatment in patients with essential hypertension did not modify the percentage change in the left main coronary artery diameter caused by sublingual administration of nitroglycerin (23.2 14.4% versus 27.2 13.5, P=0.2)., Conclusions: The present study demonstrates that treatment with the angiotensin II type 1 receptor antagonist losartan normalized the response of the left main coronary artery to the cold pressor test in patients with mild to moderate essential hypertension, and that this effect is not dependent on the reduction of blood pressure.

The speckle tracking strain is becoming a frequently used marker of subclinical left ventricular systolic dysfunction. Despite the wide range of data concerning left ventricular strain variability in the general population and its changes in various pathologic conditions, the information about the impact of medical therapy on left ventricle strain is limited. This article provides an analysis of published studies of left ventricle strain changes in response to different agents and combinations of medical therapies used for hypertension and congestive heart failure., (© 2022 Wiley Periodicals LLC.)

Aims: The prevalence and prognostic implications of coronary artery disease (CAD) in patients infected by the novel coronavirus 2019 (COVID-19) disease remain unclear., Methods: We conducted a systematic review and meta-analysis to investigate the prevalence and mortality risk in COVID-19 patients with preexisting CAD. We searched Medline and Scopus to locate all articles published up to December 8, 2021, reporting data of COVID-19 survivors and nonsurvivors with preexisting CAD. Data were pooled using the Mantel-Haenszel random effects models with odds ratio (OR) as the effect measure with the related 95% confidence interval (CI)., Results: Thirty-eight studies including 27 435 patients (mean age 61.5 and 70.9 years) were analysed. The pooled prevalence of preexisting CAD was 12.6% (95% CI: 11.2-16.5%, I2 : 95.6%), and resulted as higher in intensive care unit patients (17.5%, 95% CI: 11.9-25.1, I2 : 88.4%) and in European cohorts (13.1%, 95% CI: 7.8-21.6%, P  < 0.001, I2 : 98.4%). COVID-19 patients with preexisting CAD had a two-fold risk of short-term mortality (OR 2.61, 95% CI 2.10-3.24, P  < 0.001, I2  = 73.6%); this risk was higher among Asian cohorts (OR: 2.66, 95% CI: 1.79-3.90, P  < 0.001, I2 : 77.3%) compared with European (OR: 2.44, 95% CI: 1.90-3.14, P  < 0.001, I2 : 56.9%) and American (OR: 1.86, 95% CI: 1.41-2.44, P  < 0.001, I2 : 0%) populations. The association between CAD and poor short-term prognosis was influenced by age, prevalence of hypertension (HT), DM and CKD., Conclusions: Preexisting CAD is present in approximately 1 in 10 patients hospitalized for COVID-19 and significantly associated with an increased risk of short-term mortality, which is influenced by age, HT, DM and CKD., (Copyright © 2022 Italian Federation of Cardiology - I.F.C. All rights reserved.)

Objective: 20-Hydroxyeicosatetraenoic acid (20-HETE) is a vasoactive eicosanoid exhibiting effects on vascular smooth muscle cell (VSMC) via G-protein coupled receptor 75 (GPR75) and include stimulation of contractility, migration, and growth. We examined whether VSMC-targeted overexpression of CYP4A12, the primary 20-HETE-producing enzyme in mice, is sufficient to promote hypertension., Methods: Mice with VSM-specific Cyp4a12 overexpression (Myh11-4a12) and their littermate controls (WT) were generated by crossbreeding Cyp4a12-floxed with Myh11-Cre mice. The 20-HETE receptor blocker, N-disodium succinate-20-hydroxyeicosa-6(Z),15(Z)-diencarboxamide (AAA), was administered in the drinking water. Experiments were carried out for 12 days. SBP was measured by tail cuff. Renal interlobar and mesenteric arteries were harvested for assessment of gene expression, 20-HETE levels, vascular contractility, vasodilation, and remodeling., Results: Vascular and circulatory levels of 20-HETE were several folds higher in Myh11-4a12 mice compared with WT. The Myh11-4a12 mice compared with WT were hypertensive (145 ± 2 vs. 127 ± 2 mmHg; P < 0.05) and their vasculature displayed a contractile phenotype exemplified by increased contractility, reduced vasodilatory capacity, and increased media to lumen ratio. All these features were reversed by the administration of AAA. The mechanism of increased contractility includes, at least in part, Rho-kinase activation followed by increased myosin light chain phosphorylation and activation of the contractile apparatus., Conclusion: VSM-specific Cyp4a12 overexpression is sufficient to alter VSM cell phenotype through changes in contractile markers and enhancement in contractility that promote hypertension and vascular dysfunction in a 20-HETE-dependent manner. The 20-HETE receptor GPR75 may represent a novel target for the treatment of hypertension and associated vascular conditions., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Hypertension is associated with more severe disease and adverse outcomes in COVID-19 patients. Recent investigations have indicated that hypertension might be an independent predictor of outcomes in COVID-19 patients regardless of other cardiovascular and noncardiovascular comorbidities. We explored the significance of coronary calcifications in 694 hypertensive patients in the Score-COVID registry, an Italian multicenter study conducted during the first pandemic wave in the Western world (March-April 2020). A total of 1565 patients admitted with RNA-PCR-positive nasopharyngeal swabs and chest computed tomography (CT) at hospital admission were included in the study. Clinical outcomes and cardiovascular calcifications were analyzed independently by a research core lab. Hypertensive patients had a different risk profile than nonhypertensive patients, with more cardiovascular comorbidities. The deceased hypertensive patients had a greater coronary calcification burden at the level of the anterior descending coronary artery. Hypertension status and the severity cutoffs of coronary calcifications were used to stratify the clinical outcomes. For every 100-mm 3 increase in coronary calcium volume, hospital mortality in hypertensive patients increased by 8%, regardless of sex, age, diabetes, creatinine, and lung interstitial involvement. The coronary calcium score contributes to stratifying the risk of complications in COVID-19 patients. Cardiovascular calcifications appear to be a promising imaging marker for providing pathophysiological insight into cardiovascular risk factors and COVID-19 outcomes., (© 2021. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

Hypertensive heart disease (HHD) includes left ventricular (LV) functional and structural remodeling. For a long time, this involved only LV diastolic dysfunction and LV hypertrophy. However, development of imaging technique enabled more detailed insights into LV mechanics. Its impairment seems to be the first step in the cascade of HHD. Tissue characterization, obtained by cardiac magnetic resonance, opened a completely new chapter in the assessment of HHD. We report a case of a 47-year-old man who was referred to our department for a newly detected heart failure. CT angiography excluded relevant coronary disease and cardiac magnetic resonance revealed focuses of fibrosis in interventricular septum, in addition severely dilated LV with severely reduced ejection fraction. Considering the fact that the patient had longstanding uncontrolled arterial hypertension and that other causes of cardiac remodeling and dysfunction were excluded, we hypothesized that the multimodality imaging approach enabled prompt diagnosis of HHD., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: The recent global pandemic of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has involved more than 7 million people worldwide and been associated with more than 400,000 deaths. No clear information is known about all the potential risk factors for COVID-19 or what factors adversely influence its clinical course and mortality. Therefore, we analyzed the role of obesity, type 2 diabetes, and hypertension as risk factors for COVID-19., Methods: We identified articles for inclusion by searching PubMed and Google Scholar (last accessed 15 June 2020). Retrospective review of literature. Analysis of epidemiological data concerning obesity prevalence and COVID-19 incidence, particularly in Italy and the USA., Results: Data from several retrospective studies of prevalence showed that patients with hypertension, type 2 diabetes, and obesity may have more severe COVID-19, intensive care unit admission, and higher mortality rates, but it is not definitively clear if this is an independent association. In general, the prevalence of obesity in patients with COVID-19 seems to be the same as that of the general population throughout the world; however, obesity seems to be associated with more severe disease and mortality in younger (< 60 years) patients. Similar effects seem to occur in patients with diabetes and/or hypertension but at older ages (> 60 years). In strict connection, it has been proposed that the use of drugs inhibiting angiotensin-converting enzyme 2 (ACE-2) or dipeptidyl dipeptidase 4 (DPP-4) might influence viral activity and disease severity since ACE-2 and DPP-4 receptors mediate SARS-CoV-2 entry into the host cells; however, no evidence exists to date that shows that this may be the case., Conclusion: Overall, diabetes, hypertension, and obesity seem to negatively affect the clinical course and disease outcome in patients with COVID-19. However, these data need further confirmation by studies with more accurate data registration., (© 2021. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Introduction: Our objective was to determine the effectiveness of a perindopril/indapamide (Per/Ind) single-pill combination (SPC) in a broad range of patient profiles, including subgroups with varying hypertension severity, age and cardiovascular risk profiles., Methods: Patient data from four large prospective observational studies (FORTISSIMO, FORSAGE, PICASSO, ACES) were pooled. In each study, patients already treated for hypertension were switched to Per/Ind 10/2.5 mg SPC and systolic and diastolic blood pressure (SBP/DBP) measured at the 1-month (M1) and 3-month (M3) visits. Study endpoints included change in SBP and DBP from baseline to M1 and M3 and the percentage of patients achieving BP control (SBP/DBP < 140/90 mmHg for patients without diabetes or < 140/85 mmHg for patients with diabetes)., Results: A total of 16,763 patients were enrolled and received Per/Ind (94% received the full dose of 10/2.5). Mean patient age was 61.4 years (36% were ≥ 65 years old), 57% were women, and 16% had isolated systolic hypertension (ISH). Mean baseline office SBP/DBP was 162/94 mmHg, and mean duration of hypertension was 11 years. Cardiovascular risk factors and comorbid conditions were common in this population. Significant mean reductions in SBP (- 23 mmHg) and DBP (- 11 mmHg) were observed at M1 compared with baseline (P < 0.001), which were maintained at M3 (- 30 mmHg and - 14 mmHg, respectively). At M3, BP control was achieved by 70% of patients (78% for ISH). In patients with SBP ≥ 180 mmHg at baseline (grade III hypertension), the mean SBP/DBP decrease was - 51/- 20 mmHg and 53% achieved BP control. Per/Ind was well tolerated with an overall rate of adverse events of 1.3%, most frequently cough and dizziness at rates of 0.3% and 0.2%, respectively., Conclusion: In this hypertensive population including difficult-to-control patient subgroups, switching to Per/Ind 10/2.5 mg SPC led to rapid and important reductions in BP. BP control was achieved in 70% of patients overall in an everyday practice context.

This MiniReview reports the current knowledge about the treatment of arterial hypertension with the third-generation beta-adrenoceptor antagonist (BAA) nebivolol. Furthermore, it reviews the advantages of nebivolol compared to the earlier generation of BAAs with respect to their different pharmacological properties. Beta-adrenoceptor antagonists are a class of drugs applied for several different conditions, including hypertension and heart failure. They differ significantly in their pharmacological properties, including varying β 1 /β 2 -selectivity and/or exertion of additive effects on the heart and circulation. Although these drugs have been a part of hypertensive therapy for about 40 years, the outcome of large clinical trials has put the role of BAAs into question. However, most of these results were based on first- and second-generation BAAs and cannot be translated directly into third-generation drugs. The third-generation BAA nebivolol has the highest β 1 -selectivity seen so far, together with additional vasodilating and anti-oxidative properties. It is currently applied in the treatment of hypertension and congestive heart failure. Nebivolol has a unique pharmacological profile, despite showing similar blood pressure-lowering effects, and has certain advantages in the treatment of hypertension compared to the previous generations of BAAs. This includes significant improvements in endothelial dysfunction, central haemodynamics and the degree of erectile dysfunction in men, a neutral/beneficial metabolic profile and lastly a more favourable side effect profile. It is widely beneficial for, for example, sexually active men and patients with comorbidities such as type II diabetes mellitus, metabolic syndrome and chronic obstructive lung disorders. Whether the advantages translate to an improved long-term clinical outcome remains to be clarified, and ongoing prospective studies will show this in the future., (© 2019 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Background: Despite major primary health care (PHC) reforms in China with the 2009 launch of the National Essential Public Health Service Package, the country experiences many challenges in improving the management of non-communicable diseases in PHC facilities. "EMERALD" is a multifaceted implementation strategy to strengthen the management of hypertension and type-2 diabetes mellitus (T2DM) in PHC facilities. The study aims to: (1) examine the effectiveness of EMERALD in improving hypertension and T2DM management; (2) evaluate the implementation of the interventions; and (3) use the study findings to model the long-term health economic impact of the interventions. Methods: The EMERALD intervention components include: (1) empowerment for PHC providers through training and capacity building; (2) empowerment for patient communities through multi-media health education; and (3) empowerment for local health administrators through health data monitoring and strengthening governance of local PHC programs. An interrupted time series design will be used to determine the effectiveness of the interventions based on routinely collected health data extracted from local health information systems. The primary effectiveness outcome is the guideline-recommended treatment rates for people with hypertension and T2DM. Secondary effectiveness outcomes include hypertension and T2DM diagnosis and control rates, and enrolment and adherence rates to the recommended care processes in the National Essential Public Health Service Package. A mixed-methods process evaluation will be conducted to evaluate the implementation of the interventions, including the reach of the target population, adequacy of adoption, level of implementation fidelity, and maintenance. Qualitative interviews with policy makers, health administrators, PHC providers, and patients with hypertension and/or T2DM will be conducted to further identify factors influencing the implementation. In addition, health economic modelling will be performed to explore the long-term incremental costs and benefits of the interventions. Discussion: This study is expected to generate important evidence on the effectiveness, implementation, and health economic impact of complex PHC interventions to strengthen the primary care sector's contribution to addressing the growing burden of non-communicable diseases in China. Trial registration: The study has been registered on Chinese Clinical Trial Registry at https://www.chictr.org.cn/ (Registration number ChiCTR2400082036, on March 19th 2024). [ABSTRACT FROM AUTHOR]

Hypertension has become a major contributor to the morbidity and mortality of cardiovascular diseases worldwide. Despite the evidence of the anti‐hypertensive effect of gastrodia‐uncaria granules (GUG) in hypertensive patients, little is known about its potential therapeutic targets as well as the underlying mechanism. GUG components were sourced from TCMSP and HERB, with bioactive ingredients screened. Hypertension‐related targets were gathered from DisGeNET, OMIM, GeneCards, CTD, and GEO. The STRING database constructed a protein–protein interaction network, visualized by Cytoscape 3.7.1. Core targets were analyzed via GO and KEGG using R package ClusterProfiler. Molecular docking with AutodockVina 1.2.2 revealed favorable binding affinities. In vivo studies on hypertensive mice and rats validated network pharmacology findings. GUG yielded 228 active ingredients and 1190 targets, intersecting with 373 hypertension‐related genes. PPI network analysis identified five core genes: AKT1, TNF‐α, GAPDH, IL‐6, and ALB. Top enriched GO terms and KEGG pathways associated with the anti‐hypertensive properties of GUG were documented. Molecular docking indicated stable binding of core components to targets. In vivo study showed that GUG could improve vascular relaxation, alleviate vascular remodeling, and lower blood pressure in hypertensive animal models possibly through inhibiting inflammatory factors such as AKT1, mTOR, and CCND1. Integrated network pharmacology and in vivo experiment showed that GUG may exert anti‐hypertensive effects by inhibiting inflammation response, which provides some clues for understanding the effect and mechanisms of GUG in the treatment of hypertension. [ABSTRACT FROM AUTHOR]