Hypertension最新文献

{"title":"GWAS for Defining the Etiology of Hypertension: Have They Delivered?","authors":"Matthew R Alexander, Todd L Edwards, David G Harrison","doi":"10.1161/HYPERTENSIONAHA.124.23451","DOIUrl":"10.1161/HYPERTENSIONAHA.124.23451","url":null,"abstract":"<p><p>Genome-wide association studies have identified >3500 associated single nucleotide polymorphisms and over 1000 independent loci associated with hypertension. These individually have small effect sizes, and few associated loci have been experimentally tested for causal roles in hypertension using animal models or in humans. Thus, methods to prioritize and maximize the relevance of identified single nucleotide polymorphisms and associated loci are critical to determine their importance in hypertension. We propose several approaches to aid in these efforts, including: (1) integration of genome-wide association study data with multiomic data sets, including proteomics, transcriptomics, and epigenomics, (2) utilizing linked clinical and genetic data sets to determine genetic contributions to hypertension subphenotypes with distinct drivers, and (3) performing whole exome/genome sequencing on cohorts of individuals with severe hypertension to enrich for rare variants with larger effect sizes. Rather than creating longer lists of hypertension-associated single nucleotide polymorphisms, these approaches are needed to identify key mediators of hypertension pathophysiology.</p>","PeriodicalId":13042,"journal":{"name":"Hypertension","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143399100","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prenatal Psychosocial Stressors and Blood Pressure Across 4 Years Postpartum.","authors":"Noelle Pardo, Sandrah P Eckel, Zhongzheng Niu, Rima Habre, Tingyu Yang, Xinci Chen, Mario Vigil, Brendan Grubbs, Laila Al-Marayati, Nathana Lurvey, Claudia Toledo-Corral, Jill Johnston, Genevieve Dunton, Carrie Breton, Theresa M Bastain, Shohreh F Farzan","doi":"10.1161/HYPERTENSIONAHA.124.23979","DOIUrl":"10.1161/HYPERTENSIONAHA.124.23979","url":null,"abstract":"<p><strong>Background: </strong>Psychosocial stress is a cardiovascular risk factor; however, little is known about whether prenatal psychosocial stressors influence postpartum cardiovascular health. We aimed to examine the associations of multiple measures of prenatal psychosocial stress on maternal blood pressure (BP) in the first 4 years after birth.</p><p><strong>Methods: </strong>Among 225 MADRES cohort (Maternal and Developmental Risks From Environmental and Social Stressors) participants, we examined associations of average prenatal Perceived Stress Scale (PSS), Center for Epidemiological Studies Depression (CES-D) scores, and second-trimester neighborhood social cohesion scores on systolic and diastolic BP collected at annual postpartum study visits (1-4 years) using linear mixed-effects models, adjusted for covariates.</p><p><strong>Results: </strong>Higher prenatal PSS and CES-D scores were associated with greater diastolic BP at 1 year postpartum (0.24 [95% CI, 0.01-0.46] and 0.24 [95% CI, 0.08-0.40] mm Hg per 1-unit higher PSS and CES-D, respectively) and greater systolic BP (0.25 [95% CI, 0.02-0.48] mm Hg per 1-unit higher CES-D). Overall associations of PSS and CES-D with BP were attenuated over the 4-year postpartum period (<i>P</i><0.05). Stratified analyses suggested larger associations of PSS and CES-D among US-born participants and participants with normotensive pregnancies. While neighborhood social cohesion was not associated with postpartum BP overall, higher neighborhood social cohesion scores were associated with lower BP at 1 year postpartum among participants with normotensive pregnancies and lower systolic BP among foreign-born Hispanic participants.</p><p><strong>Conclusions: </strong>Higher prenatal perceived stress and depressive symptoms were associated with greater 1-year postpartum BP, whereas neighborhood cohesion was associated with lower 1-year postpartum BP. These results suggest prenatal psychosocial factors may impact cardiovascular health within the first year after birth.</p>","PeriodicalId":13042,"journal":{"name":"Hypertension","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143382010","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MYSM1 Mediates Cardiac Parthanatos and Hypertrophy by Deubiquitinating PARP1.","authors":"Xin Zhong, Jianjiang Xu, Xiaowen Shi, Yiting Lyu, Yuanyuan Qian, Zimin Fang, Zixuan Wang, Jincheng Xing, Bozhi Ye, Jiajun Xu, Jibo Han","doi":"10.1161/HYPERTENSIONAHA.124.23823","DOIUrl":"https://doi.org/10.1161/HYPERTENSIONAHA.124.23823","url":null,"abstract":"<p><strong>Background: </strong>Cardiac hypertrophy constitutes the primary pathological basis for heart failure and exerts a considerable influence on morbidity and mortality. Deubiquitinating enzymes are crucial regulators of protein degradation and play a pivotal role in cardiac pathophysiology. This study aimed to clarify the involvement of a deubiquitinating enzyme, MYSM1 (Myb-like, SWIRM, and MPN domains 1), in cardiac hypertrophy and to explore the underlying mechanism.</p><p><strong>Methods: </strong>Cardiac hypertrophy was developed by angiotensin II or transverse aortic constriction surgery. Cardiomyocyte-specific knockdown of MYSM1 was accomplished using the adeno-associated virus serotype 9-<i>cTNT</i>-<i>Mysm1</i>-shRNA. Co-immunoprecipitation combined with liquid chromatography-tandem mass spectrometry analysis was utilized to identify potential substrates of MYSM1.</p><p><strong>Results: </strong>First, we discovered that the expression of MYSM1 increases during cardiac hypertrophy. MYSM1 knockdown mitigated cardiac dysfunction and hypertrophy after angiotensin II administration. Cardiomyocyte-specific knockdown of MYSM1 with adeno-associated virus serotype 9 alleviated myocardial dysfunction and hypertrophy caused by transverse aortic constriction surgery. Through co-immunoprecipitation and LC-MS, poly (ADP-ribose) polymerase 1 (PARP1) was identified as a potential substrate protein of MYSM1. PARP1 initiates a novel form of programmed cell death termed parthanatos, which is characterized by excessive PARylation, nuclear translocation of AIF, and depletion of nicotinamide adenine dinucleotide. MYSM1 deubiquitinates and stabilizes PARP1 in an MPN domain-dependent manner. In addition, MYSM1 mediates cardiac hypertrophy through PARP1-dependent cardiomyocyte parthanatos.</p><p><strong>Conclusions: </strong>This study identified the role of the MYSM1-PARP1 axis in mediating cardiac hypertrophy and suggested that MYSM1 is a promising pharmacological target for the treatment of cardiac hypertrophy.</p>","PeriodicalId":13042,"journal":{"name":"Hypertension","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143189194","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Autonomous Epinephrine Release by KCNJ5 Mutation Drives Familial Thoracic Aortic Aneurysm and Dissection.","authors":"Yanyu Duan, Chenglong Wu, Zhenghong Lai, Qunxing Yuan, Naixing Hu, Shaoqiang Liu, Ziyou Liu","doi":"10.1161/HYPERTENSIONAHA.124.23795","DOIUrl":"https://doi.org/10.1161/HYPERTENSIONAHA.124.23795","url":null,"abstract":"<p><strong>Background: </strong>The pathophysiology of familial thoracic aortic aneurysm and dissection (TAAD) is linked to genetic variants that affect aortic components. Although hypertension is a risk factor for TAAD, the precise genetic link remains unclear.</p><p><strong>Methods: </strong>A family with autosomal dominant TAAD complicated by hypertension was studied to identify candidate mutations. The effect of the identified mutation on TAAD development was investigated using a CRISPR-Cas9-generated knock-in mouse model to elucidate the mechanism underlying hypertension-induced TAAD.</p><p><strong>Results: </strong>The <i>KCNJ5 p.R242Q</i> mutation was identified in the family and met the criteria for cosegregation, rarity, and conservation. Utilizing our mouse model, we observed that a significant proportion of heterozygous mice with the mutation displayed dilated thoracic aortas. The mutation's allele dose was positively correlated with TAAD incidence following β-aminopropionitrile monofumarate treatment. Pathological changes in the thoracic aorta, including collagen deposition and dilation, elevated transforming growth factor-β activity, and extracellular matrix remodeling, were associated with hypertension. Furthermore, the mutation was found to induce lifelong isolated systolic hypertension, attributable to autonomous epinephrine secretion from the adrenal medulla. Unlike wild-type, mutated <i>KCNJ5</i> was highly expressed in the adrenal medulla instead of the adrenal cortex. Treatment with the adrenergic β-receptor blocker propranolol reduced systolic hypertension and mitigated TAAD in the heterozygous mice.</p><p><strong>Conclusions: </strong>Familial TAAD may stem from <i>KCNJ5</i> dysfunction in the G-protein-coupling domain, causing isolated systolic hypertension via increased epinephrine secretion and disruption of thoracic aortic homeostasis. These findings establish a genetic link between systolic hypertension and TAAD.</p>","PeriodicalId":13042,"journal":{"name":"Hypertension","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143189190","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Downregulated PSME3 Contributes to Severe Preeclampsia by Promoting Trophoblast Cell Apoptosis.","authors":"Lin Liu, Hui Chen, Renfei Wu, Qiongyao Wang, Qiujing Guan, Yang Chen, Siyuan Cao, Longying Tang, Zaijun Lin, Lei Li, Xiaoli Ge","doi":"10.1161/HYPERTENSIONAHA.124.22718","DOIUrl":"https://doi.org/10.1161/HYPERTENSIONAHA.124.22718","url":null,"abstract":"<p><strong>Background: </strong>Severe preeclampsia (sPE) is a serious condition posing risks to both maternal and fetal health. Based on mass spectrometry analysis, we identified a key protein, PSME3 (proteasome activator subunit 3), an 11S proteasome activator, whose protein level was significantly downregulated in sPE placentas and whose function in sPE remains unknown.</p><p><strong>Methods: </strong>PSME3 protein levels in human placental tissue were detected using Western blot, and PSME3 concentration in serum was detected by ELISA assay. The human preeclampsia-like phenotypes of <i>Psme3</i>^-^<i>/</i>- pregnant mice were examined. Trophoblast cell apoptosis was detected by flow cytometry. Pregnant mice were treated with 9.5% O₂ to construct a preeclampsia mouse model for detecting placental Psme3 expression. The regulation of PSME3 expression by hypoxia was detected in trophoblast cell lines treated with 21% O₂ or 1% O₂.</p><p><strong>Results: </strong>PSME3 protein levels were significantly downregulated in sPE placentas and serum. Pregnant mice with <i>Psme3</i>^-<i>/</i>- embryos and placentas spontaneously presented human preeclampsia-like symptoms, including hypertension and proteinuria, increased serum soluble fms-like tyrosine kinase 1 concentration, fetal growth restriction, and increased cellular apoptosis. Mechanically, PSME3 knockdown promoted the apoptosis of trophoblast cells by repressing the degradation of UBE2V2 (ubiquitin conjugating enzyme E2 V2). Moreover, the placentas of hypoxia-induced preeclampsia mice presented significantly reduced Psme3 protein levels and elevated Ube2v2 protein levels. Hypoxia-inducible factor-1α functioned as a transcriptional repressor of PSME3.</p><p><strong>Conclusions: </strong>In sPE placentas, hypoxia of the placenta may lead to the transcriptional inhibition of PSME3. PSME3 deficiency promotes the accumulation of UBE2V2, thereby inducing trophoblast cell apoptosis. Our study provides a new perspective for elucidating the pathogenesis of sPE.</p>","PeriodicalId":13042,"journal":{"name":"Hypertension","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143189192","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Central Interaction of 2-Methoxyestradiol and Lipoxygenase in AngII-Hypertension.","authors":"Shubha R Dutta, Purnima Singh, Chi Young Song, Ji Soo Shin, Kafait U Malik","doi":"10.1161/HYPERTENSIONAHA.124.23905","DOIUrl":"https://doi.org/10.1161/HYPERTENSIONAHA.124.23905","url":null,"abstract":"<p><strong>Background: </strong>Our previous findings that arachidonic acid-12/15-lipoxygenase (LOX)-generated metabolite 12(S)-HETE contributes to angiotensin II (AngII)-induced hypertension and 17β-estradiol protects from AngII-induced hypertension via its cytochrome P450 (CYP)1B1-generated metabolite 2-methoxyestradiol in the paraventricular nucleus (PVN) in female mice led us to test the hypothesis that 2-methoxyestradiol acts by inhibiting the LOX/12(S)-HETE in the PVN.</p><p><strong>Methods: </strong>AngII was infused subcutaneously by osmotic pumps for 2 weeks in wild-type, LOX-knockout (LOXKO), and CYP1B1KO female mice. The blood pressure was measured by tail-cuff/radiotelemetry. Adenovirus (Ad)-GFP (green fluorescence protein)-LOX-short hairpin (sh)RNA, Ad-GFP-LOX-DNA, 12(S)-HETE, and 2-methoxyestradiol were injected selectively in PVN or intracerebroventricularly. Histological, immunohistochemical, and biochemical techniques were used to determine pathophysiological changes caused by various interventions.</p><p><strong>Results: </strong>AngII-induced hypertension that was exaggerated in CYP1B1KO compared with wild-type mice was minimized by PVN-LOX knockdown with Ad-LOX-short hairpin RNA and restored by PVN-LOX reconstitution with Ad-LOX-DNA in intact-LOXKO mice and exacerbated in ovariectomized-LOXKO mice. Furthermore, intracerebroventricular-12(S)-HETE restored AngII-induced increases in blood pressure, autonomic impairment, neuroinflammation, and renal pathogenesis in intact-LOXKO mice, which were exacerbated in ovariectomized-LOXKO mice. Intracerebroventricular-2-methoxyestradiol that reduced the LOX expression and 12(S)-HETE content in PVN minimized AngII effects mentioned above in ovariectomized-LOXKO mice transduced intracerebroventricular-Ad-LOX-DNA.</p><p><strong>Conclusions: </strong>These data suggest that 2-methoxyestradiol protects against AngII-induced hypertension and associated pathogenesis, most likely by inhibiting LOX/12(S)-HETE actions in the PVN of female mice. Therefore, the selective LOX inhibitors or 12(S)-HETE receptor antagonists could be useful in treating hypertension and its pathogenesis in postmenopausal, hypoestrogenic women or females with ovarian failure.</p>","PeriodicalId":13042,"journal":{"name":"Hypertension","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143122787","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Associations of Lipid-Lowering Drugs With Blood Pressure and Fasting Glucose: A Mendelian Randomization Study.","authors":"Beiping Song, Lulu Sun, Xiaoli Qin, Jiawen Fei, Quan Yu, Xinyue Chang, Yu He, Yi Liu, Mengyao Shi, Daoxia Guo, Ouxi Shen, Zhengbao Zhu","doi":"10.1161/HYPERTENSIONAHA.124.23829","DOIUrl":"https://doi.org/10.1161/HYPERTENSIONAHA.124.23829","url":null,"abstract":"<p><strong>Background: </strong>Observational studies have linked LDL-C (low-density lipoprotein-cholesterol)-lowering drugs with lower blood pressure (BP) and higher fasting glucose, but the causality remains unclear. We conducted a drug target Mendelian randomization study to assess the causal associations of genetically proxied inhibition of HMGCR (3-hydroxy-3-methylglutaryl coenzyme A reductase), PCSK9 (proprotein convertase subtilisin/kexin type 9), and NPC1L1 (Niemann-Pick C1-Like 1) with BP and fasting glucose.</p><p><strong>Methods: </strong>Single-nucleotide polymorphisms in <i>HMGCR</i>, <i>NPC1L1</i>, and <i>PCSK9</i> associated with LDL-C in a genome-wide association study meta-analysis from the Global Lipid Genetics Consortium (173 082 European individuals) were used to proxy LDL-C-lowering drug targets. BP and fasting glucose data were obtained from genome-wide association studies conducted by the International Consortium of Blood Pressure (757 601 European participants) and the Glucose and Insulin-related Traits Consortium (58 074 European participants). We used the inverse-variance weighted method and a series of sensitivity analyses for assessment.</p><p><strong>Results: </strong>Genetically proxied inhibition of HMGCR was negatively associated with systolic BP (β, -0.81 [95% CI, -1.26 to -0.37 mm Hg]; <i>P</i>=3.72×10^-⁴) and diastolic BP (β, -1.58 [95% CI, -2.24 to -0.91 mm Hg]; <i>P</i>=3.23×10^-⁶). Conversely, we observed a positive association between genetically proxied inhibition of HMGCR and high fasting glucose (β, 0.13 [95% CI, 0.08-0.17 mmol/L]; <i>P</i>=4.25×10^-⁸). However, there was no association of PCSK9 and NPC1L1 inhibition with BP or fasting glucose.</p><p><strong>Conclusions: </strong>Genetically proxied inhibition of HMGCR was significantly associated with low BP and high fasting glucose, while there was no effect of PCSK9 and NPC1L1 inhibition on BP or fasting glucose.</p>","PeriodicalId":13042,"journal":{"name":"Hypertension","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143122773","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cross-Sex Hormone Therapy Is Associated With Loss of Circadian Rhythm in the Male Rat.","authors":"Jordan H Mallette, Breland F Crudup, Adrian Oudomrath Speyrer, Adam Z Rawls, Kathy Cockrell, Alex T Willis, Kacey Davenport, Licy L Yanes Cardozo, Noha M Shawky, Barbara T Alexander","doi":"10.1161/HYPERTENSIONAHA.124.23901","DOIUrl":"10.1161/HYPERTENSIONAHA.124.23901","url":null,"abstract":"<p><strong>Background: </strong>Transgender women are individuals born male but identify as female. Many transgender women undergo gender-affirming hormone therapy to alleviate the distress that can occur due to gender incongruence. For transgender women, gender-affirming hormone therapy includes 17β-estradiol (E2) combined with an antiandrogen therapy (AA) or surgical intervention. Numerous studies suggest that the risk of cardiovascular disease is elevated in transgender women; yet, the biological effects of gender-affirming hormone therapy on cardiovascular health are unknown. We hypothesize that a shift in the hormonal milieu versus natal sex in the male rat is associated with an increase in blood pressure at baseline and an enhanced responsiveness to a hypertensive challenge.</p><p><strong>Methods: </strong>We developed clinically relevant models that mimic gender-affirming hormone therapy combination therapies utilized for the endocrine treatment of gender dysphoria in transgender women.</p><p><strong>Results: </strong>Chronic E2 plus castration or the E2+antiandrogen spironolactone was associated with a significant reduction in lean mass and testosterone. At baseline, 24-hour mean arterial pressure did not differ in E2+castration or E2+antiandrogen therapy versus control, but circadian rhythm was disrupted. In response to chronic Ang II (angiotensin II; 200 ng/kg per minute), the Ang II-induced increase in blood pressure was attenuated in E2+castration compared with control, but the blood pressure response to Ang II was similar in E2+antiandrogen therapy versus control.</p><p><strong>Conclusions: </strong>Thus, these data indicate that the type of combination therapy utilized may exert differential effects on blood pressure and that disruption of circadian rhythm may be a contributory factor to the increased risk of adverse cardiovascular outcomes in transgender women exposed to high 17β-estradiol coupled to androgen suppression.</p>","PeriodicalId":13042,"journal":{"name":"Hypertension","volume":" ","pages":"241-254"},"PeriodicalIF":6.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11735301/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142780176","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ACE2, From the Kidney to SARS-CoV-2: Donald Seldin Award Lecture 2023.","authors":"Daniel Batlle, Luise Hassler, Jan Wysocki","doi":"10.1161/HYPERTENSIONAHA.124.22064","DOIUrl":"10.1161/HYPERTENSIONAHA.124.22064","url":null,"abstract":"<p><p>ACE2 (angiotensin-converting enzyme 2) is a monocarboxypeptidase that cleaves Ang II (angiotensin II) among other substrates. ACE2 is present in the cell membrane of many organs, most abundantly in epithelial cells of kidney proximal tubules and the small intestine, and also exists in soluble forms in plasma and body fluids. Membrane-bound ACE2 exerts a renoprotective action by metabolizing Ang II and therefore attenuating the undesirable actions of excess Ang II. Therefore, soluble ACE2, by downregulating this peptide, may exert a therapeutic action. Our laboratory has designed ACE2 truncates that pass the glomerular filtration barrier to target the kidney renin-angiotensin system directly and, therefore, compensate for loss of kidney membrane-bound ACE2. Membrane-bound ACE2 is also the essential receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Soluble ACE2 proteins have been studied as a way to intercept SARS-CoV-2 from binding to membrane-bound ACE2 and prevent cell entry of SARS-CoV-2 altogether. We bioengineered a soluble ACE2 protein, termed ACE2 618-DDC-ABD, with increased binding affinity for SARS-CoV-2 and prolonged duration of action, which, when administered intranasally, provides near-complete protection from lethality in k18hACE2 mice infected with different SARS-CoV-2 variants. The main advantage of soluble ACE2 proteins for the neutralization of SARS-CoV-2 is their immediate onset of action and universality for current and future emerging SARS-CoV-2 variants. It is notable that ACE2 is critically involved in 2 dissimilar functions: as a receptor for cell entry of many coronaviruses and as an enzyme in the metabolism of Ang II, and yet in both cases, it is a therapeutic target.</p>","PeriodicalId":13042,"journal":{"name":"Hypertension","volume":" ","pages":"166-180"},"PeriodicalIF":6.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142768559","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cost-Effectiveness of Intensive Blood Pressure Control in Youth With Chronic Kidney Disease.","authors":"Carol L Vincent, Katherine A Poehling, Joseph Rigdon, Christopher L Schaich, Andrew M South, Stephen M Downs","doi":"10.1161/HYPERTENSIONAHA.124.23437","DOIUrl":"10.1161/HYPERTENSIONAHA.124.23437","url":null,"abstract":"<p><strong>Background: </strong>Intensive blood pressure (BP) control in youth with chronic kidney disease (CKD) slows progression, delaying the need for kidney replacement therapy (KRT). Most youth with CKD have hypertension and BP control is difficult to achieve outside of controlled experimental settings. Implementing effective BP control strategies in this population may be cost-saving despite requiring additional resources. Our objective was to determine the economic and clinical impact of intensive versus usual care for BP management in youth with CKD in a microeconomic model.</p><p><strong>Methods: </strong>We developed a decision tree from the US payer perspective to estimate the total costs and clinical effect of an intensified BP intervention over 5 years, modeled after the ESCAPE trial (Effect of Strict Blood Pressure Control and Angiotensin-Converting Enzyme [ACE] Inhibition on Progression of Chronic Renal Failure in Pediatric Patients) protocol. We compared this intervention to usual care in a hypothetical population of youth with mild-to-moderate CKD. Probabilities were informed by published literature; cost estimates were informed by publicly available data. Our outcomes were the net discounted cost of an intensive BP intervention, number needed to treat with the intervention to prevent 1 KRT episode, and incremental cost per KRT episode avoided.</p><p><strong>Results: </strong>An intensive BP intervention, with a goal of an average 24-hour mean arterial pressure <50th percentile, improved outcomes with net cost savings of $9440 per participant over 5 years compared with usual care. To prevent 1 episode of KRT over 5 years, 13 participants need to receive intensive BP intervention.</p><p><strong>Conclusions: </strong>Routine use of the ESCAPE protocol for intensive BP control in youth with CKD could save overall costs for the payer and improve clinical outcomes.</p>","PeriodicalId":13042,"journal":{"name":"Hypertension","volume":" ","pages":"393-401"},"PeriodicalIF":6.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11796311/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142780203","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}