Hypertension最新文献

{"title":"Cardiac Effects of Renin-Angiotensin System Inhibitors in Nonproteinuric CKD.","authors":"Rachel S Shulman, Wei Yang, Debbie L Cohen, Peter P Reese, Jordana B Cohen","doi":"10.1161/HYPERTENSIONAHA.124.23184","DOIUrl":"10.1161/HYPERTENSIONAHA.124.23184","url":null,"abstract":"<p><strong>Background: </strong>In contrast to proteinuric chronic kidney disease (CKD), the relative cardioprotective benefits of antihypertensive medications in nonproteinuric CKD are unknown. We examined long-term cardiovascular outcomes and mortality in patients with nonproteinuric CKD treated with renin-angiotensin system inhibitors (RASIs) versus other antihypertensive medications.</p><p><strong>Methods: </strong>Among participants of the CRIC study (Chronic Renal Insufficiency Cohort) without proteinuria, we used intention-to-treat analyses with inverse probability of treatment weighting and Cox proportional hazards modeling to determine the association of RASIs versus other antihypertensive medications with a composite cardiovascular outcome (myocardial infarction, stroke, heart failure hospitalization, and death) and mortality. Secondary analyses included per-protocol analyses accounting for continuous adherence and time-updated analyses accounting for the proportion of time using RASIs during follow-up.</p><p><strong>Results: </strong>A total of 2806 participants met the inclusion criteria. In the intention-to-treat analyses, RASIs versus other antihypertensive medications were not associated with an appreciable difference in cardiovascular events (adjusted hazard ratio [aHR], 0.94 [95% CI, 0.80-1.11]) or mortality (aHR, 1.06 [95% CI, 0.88-1.28]). In the per-protocol analyses, RASIs were associated with a lower risk of adverse cardiovascular events (aHR, 0.78 [95% CI, 0.63-0.97]) and mortality (aHR, 0.64 [95% CI, 0.48-0.85]). Similarly, in the time-updated analyses, a higher proportion of RASI use over time was associated with a lower mortality risk (aHR, 0.33 [95% CI, 0.14-0.86]).</p><p><strong>Conclusions: </strong>Among individuals with nonproteinuric CKD, after accounting for time-updated use, RASIs are associated with fewer cardiovascular events and a lower mortality risk compared with other antihypertensive medications. Patients with nonproteinuric CKD may benefit from prioritizing RASIs for hypertension management.</p>","PeriodicalId":13042,"journal":{"name":"Hypertension","volume":" ","pages":"2082-2090"},"PeriodicalIF":6.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11410532/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141859617","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":"Renal Denervation for the Treatment of Hypertension: A Scientific Statement From the American Heart Association.","authors":"Jennifer L Cluett, Olivia Blazek, Angela L Brown, Cara East, Keith C Ferdinand, Naomi D L Fisher, Cassandra D Ford, Karen A Griffin, Carlos I Mena-Hurtado, Harini Sarathy, Wanpen Vongpatanasin, Raymond R Townsend","doi":"10.1161/HYP.0000000000000240","DOIUrl":"10.1161/HYP.0000000000000240","url":null,"abstract":"<p><p>Hypertension is a leading risk factor for cardiovascular morbidity and mortality. Despite the widespread availability of both pharmacological and lifestyle therapeutic options, blood pressure control rates across the globe are worsening. In fact, only 23% of individuals with high blood pressure in the United States achieve treatment goals. In 2023, the US Food and Drug Administration approved renal denervation, a catheter-based procedure that ablates the renal sympathetic nerves, as an adjunctive treatment for patients in whom lifestyle modifications and antihypertensive medications do not adequately control blood pressure. This approval followed the publication of multiple randomized clinical studies using rigorous trial designs, all incorporating renal angiogram as the sham control. Most but not all of the new generation of trials reached their primary end point, demonstrating modest efficacy of renal denervation in lowering blood pressure across a spectrum of hypertension, from mild to truly resistant. Individual patient responses vary, and further research is needed to identify those who may benefit most. The initial safety profile appears favorable, and multiple ongoing studies are assessing longer-term efficacy and safety. Multidisciplinary teams that include hypertension specialists and adequately trained proceduralists are crucial to ensure that referrals are made appropriately with full consideration of the potential risks and benefits. Incorporating patient preferences and engaging in shared decision-making conversations will help patients make the best decisions given their individual circumstances. Although further research is clearly needed, renal denervation presents a novel treatment strategy for patients with uncontrolled blood pressure.</p>","PeriodicalId":13042,"journal":{"name":"Hypertension","volume":" ","pages":"e135-e148"},"PeriodicalIF":6.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141889007","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":"Effects of Oral Butyrate on Blood Pressure in Patients With Hypertension: A Randomized, Placebo-Controlled Trial.","authors":"Barbara J H Verhaar, Madelief Wijdeveld, Koen Wortelboer, Elena Rampanelli, Johannes H M Levels, Didier Collard, Marianne Cammenga, Vanasa Nageswaran, Arash Haghikia, Ulf Landmesser, Xinmin S Li, Joseph A DiDonato, Stanley L Hazen, Ingrid M Garrelds, A H Jan Danser, Bert-Jan H van den Born, Max Nieuwdorp, Majon Muller","doi":"10.1161/HYPERTENSIONAHA.123.22437","DOIUrl":"10.1161/HYPERTENSIONAHA.123.22437","url":null,"abstract":"<p><strong>Background: </strong>The microbiota-derived short chain fatty acid butyrate has been shown to lower blood pressure (BP) in rodent studies. Nonetheless, the net effect of butyrate on hypertension in humans remains uncovered. In this study, for the first time, we aimed to determine the effect of oral butyrate on BP in patients with hypertension.</p><p><strong>Methods: </strong>We performed a double-blind randomized placebo-controlled trial including 23 patients with hypertension. Antihypertensive medication was discontinued for the duration of the study with a washout period of 4 weeks before starting the intervention. Participants received daily oral capsules containing either sodium butyrate or placebo with an equivalent dosage of sodium chloride for 4 weeks. The primary outcome was daytime 24-hour systolic BP. Differences between groups over time were assessed using linear mixed models (group-by-time interaction).</p><p><strong>Results: </strong>Study participants (59.0±3.7 years; 56.5% female) had an average baseline office systolic BP of 143.5±14.6 mm Hg and diastolic BP of 93.0±8.3 mm Hg. Daytime 24-hour systolic and diastolic BP significantly increased over the intervention period in the butyrate compared with the placebo group, with an increase of +9.63 (95% CI, 2.02-17.20) mm Hg in daytime 24-hour systolic BP and +5.08 (95% CI, 1.34-8.78) mm Hg in diastolic BP over 4 weeks. Butyrate levels significantly increased in plasma, but not in feces, upon butyrate intake, underscoring its absorption.</p><p><strong>Conclusions: </strong>Four-week treatment with oral butyrate increased daytime systolic and diastolic BP in subjects with hypertension. Our findings implicate that butyrate does not have beneficial effects on human hypertension, which warrants caution in future butyrate intervention studies.</p><p><strong>Registration: </strong>URL: https://onderzoekmetmensen.nl/; Unique identifier: NL8924.</p>","PeriodicalId":13042,"journal":{"name":"Hypertension","volume":" ","pages":"2124-2136"},"PeriodicalIF":6.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11404767/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141733973","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":"Epigenetic Clock at Birth and Childhood Blood Pressure Trajectory: A Prospective Birth Cohort Study.","authors":"Jie Hu, Anat Yaskolka Meir, Xiumei Hong, Guoying Wang, Frank B Hu, Xiaobin Wang, Liming Liang","doi":"10.1161/HYPERTENSIONAHA.124.22695","DOIUrl":"10.1161/HYPERTENSIONAHA.124.22695","url":null,"abstract":"<p><strong>Background: </strong>The impact of methylation gestational age (GAmAge; a biomarker of fetal maturity) at birth on childhood blood pressure (BP) trajectories is unknown.</p><p><strong>Methods: </strong>This cohort study included 500 boys and 440 girls with data on cord blood DNA methylation and BP at 3 to 15 years of age. Systolic BP (SBP) and diastolic BP percentiles were calculated based on clinical guidelines. Time-series K-means clustering identified 4 distinct SBP and diastolic BP percentile trajectories: high-steady, high-decrease, normal-increase, and normal-steady. GAmAge was estimated using an existing pediatric epigenetic clock. Extrinsic age acceleration was calculated as residuals of associations between GAmAge and chronological gestational age. Intrinsic age acceleration was calculated using the same method adjusting for cord blood cell compositions.</p><p><strong>Results: </strong>Extrinsic age acceleration and intrinsic age acceleration were inversely associated with repeated measures of BP percentiles. Significant inverse associations were observed between extrinsic age acceleration and SBP percentiles in boys (β=-2.02; <i>P</i>=0.02) but not in girls (β=-0.49; <i>P</i>=0.58). Both extrinsic age acceleration and intrinsic age acceleration were inversely associated with SBP percentiles in girls born preterm (<37 weeks; β_EAA=-2.95; β_IAA=-3.00; <i>P</i><0.05). Compared with the normal-steady SBP trajectory, significant inverse associations were observed between intrinsic age acceleration and high-steady, high-decrease, and normal-increase SBP trajectories in boys (odds ratio, 0.73-0.81; <i>P</i><0.03), and significant positive associations were observed for high-decrease and normal-increase SBP trajectories in girls (odds ratio, 1.26-1.38; <i>P</i><0.01). Significant sex differences were observed (<i>P</i>_{sex-interaction}<2×10^-16).</p><p><strong>Conclusions: </strong>GAmAge acceleration at birth was inversely associated with child BP, and such association was more pronounced in boys than in girls. Our findings may shed new light on the developmental origins of high BP and sex differences in cardiovascular risk.</p>","PeriodicalId":13042,"journal":{"name":"Hypertension","volume":" ","pages":"e113-e124"},"PeriodicalIF":6.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11410530/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141859618","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":"<i>UMOD</i> Genotype-Blinded Trial of Ambulatory Blood Pressure Response to Torasemide.","authors":"Linsay McCallum, Stefanie Lip, Alex McConnachie, Katriona Brooksbank, Iain M MacIntyre, Alexander Doney, Andrea Llano, Alisha Aman, Thomas M Caparrotta, Gareth Ingram, Isla S Mackenzie, Anna F Dominiczak, Thomas M MacDonald, David J Webb, Sandosh Padmanabhan","doi":"10.1161/HYPERTENSIONAHA.124.23122","DOIUrl":"10.1161/HYPERTENSIONAHA.124.23122","url":null,"abstract":"<p><strong>Background: </strong>UMOD (uromodulin) has been linked to hypertension through potential activation of Na⁺-K⁺-2Cl^- cotransporter (NKCC2), a target of loop diuretics. We posited that hypertensive patients carrying the rs13333226-AA <i>UMOD</i> genotype would demonstrate greater blood pressure responses to loop diuretics, potentially mediated by this UMOD/NKCC2 interaction.</p><p><strong>Methods: </strong>This prospective, multicenter, genotype-blinded trial evaluated torasemide (torsemide) efficacy on systolic blood pressure (SBP) reduction over 16 weeks in nondiabetic, hypertensive participants uncontrolled on ≥1 nondiuretic antihypertensive for >3 months. The primary end point was the change in 24-hour ambulatory SBP (ABPM SBP) and SBP response trajectories between baseline and 16 weeks by genotype (AA versus AG/GG) due to nonrandomized groups at baseline (ClinicalTrials.gov: NCT03354897).</p><p><strong>Results: </strong>Of 251 enrolled participants, 222 received torasemide and 174 demonstrated satisfactory treatment adherence and had genotype data. The study participants were middle-aged (59±11 years), predominantly male (62%), obese (body mass index, 32±7 kg/m²), with normal eGFR (92±17 mL/min/1.73 m²) and an average baseline ABPM of 138/81 mm Hg. Significant reductions in mean ABPM SBP were observed in both groups after 16 weeks (AA, -6.57 mm Hg [95% CI, -8.44 to -4.69]; <i>P</i><0.0001; AG/GG, -3.22 [95% CI, -5.93 to -0.51]; <i>P</i>=0.021). The change in mean ABPM SBP (baseline to 16 weeks) showed a difference of -3.35 mm Hg ([95% CI, -6.64 to -0.05]; <i>P</i>=0.048) AA versus AG/GG genotypes. The AG/GG group displayed a rebound in SBP from 8 weeks, differing from the consistent decrease in the AA group (<i>P</i>=0.004 for difference in trajectories).</p><p><strong>Conclusions: </strong>Our results confirm a plausible interaction between UMOD and NKCC2 and suggest a potential role for genotype-guided use of loop diuretics in hypertension management.</p><p><strong>Registration: </strong>URL: https://www.clinicaltrials.gov; Unique identifier: NCT03354897.</p>","PeriodicalId":13042,"journal":{"name":"Hypertension","volume":" ","pages":"2049-2059"},"PeriodicalIF":6.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11460757/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141792339","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":"Genetic Variance in Heparan Sulfation Is Associated With Salt Sensitivity.","authors":"Jetta J Oppelaar, Bart Ferwerda, Mohamed A Romman, Ghazalah N Sahebdin, Aeilko H Zwinderman, Henrike Galenkamp, S Matthijs Boekholdt, Bert-Jan H van den Born, Rik H G Olde Engberink, Liffert Vogt","doi":"10.1161/HYPERTENSIONAHA.124.23421","DOIUrl":"10.1161/HYPERTENSIONAHA.124.23421","url":null,"abstract":"<p><strong>Background: </strong>High heritability of salt sensitivity suggests an essential role for genetics in the relationship between sodium intake and blood pressure (BP). The role of glycosaminoglycan genes, which are crucial for salinity tolerance, remains to be elucidated.</p><p><strong>Methods: </strong>Interactions between 54 126 variants in 130 glycosaminoglycan genes and daily sodium excretion on BP were explored in 20 420 EPIC-Norfolk (European Prospective Investigation Into Cancer in Norfolk) subjects. The UK Biobank (n=414 132) and the multiethnic HELIUS study (Healthy Life in an Urban Setting; n=2239) were used for validation. Afterward, the urinary glycosaminoglycan composition was studied in HELIUS participants (n=57) stratified by genotype and upon dietary sodium loading in a time-controlled crossover intervention study (n=12).</p><p><strong>Results: </strong>rs2892799 in <i>NDST3</i> (heparan sulfate N-deacetylase/N-sulfotransferase 3) showed the strongest interaction with sodium on mean arterial pressure (false discovery rate 0.03), with higher mean arterial pressure for the C allele in high sodium conditions. Also, rs9654628 in <i>HS3ST5</i> (heparan sulfate-glucosamine 3-sulfotransferase 5) showed an interaction with sodium on systolic BP (false discovery rate 0.03). These interactions were multiethnically validated. Stratifying for the rs2892799 genotype showed higher urinary expression of N-sulfated heparan sulfate epitope D0S0 for the T allele. Conversely, upon dietary sodium loading, urinary D0S0 expression was higher in participants with stable BP after sodium loading, and sodium-induced effects on this epitope were opposite in individuals with and without BP response to sodium.</p><p><strong>Conclusions: </strong>The C allele of rs2892799 in <i>NDST3</i> exhibits higher BP in high sodium conditions when compared with low sodium conditions, whereas no differences were detected for the T allele. Concomitantly, both alleles demonstrate distinct expressions of D0S0, which, in turn, correlates with sodium-mediated BP elevation. These findings underscore the potential significance of genetic glycosaminoglycan variation in human BP regulation.</p>","PeriodicalId":13042,"journal":{"name":"Hypertension","volume":" ","pages":"2101-2112"},"PeriodicalIF":6.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11404764/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142153882","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":"Lipoproteins and Exosomes as Novel Carriers of Soluble Fms-Like Tyrosine Kinase-1 and Placental Growth Factor During Pregnancy.","authors":"Lunbo Tan, Martijn H van Heugten, Ans C M Kluivers, Leonie van Vark-van der Zee, Monique T Mulder, Xifeng Lu, A H Jan Danser, Koen Verdonk","doi":"10.1161/HYPERTENSIONAHA.124.23399","DOIUrl":"10.1161/HYPERTENSIONAHA.124.23399","url":null,"abstract":"","PeriodicalId":13042,"journal":{"name":"Hypertension","volume":" ","pages":"e132-e134"},"PeriodicalIF":6.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11404752/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141792340","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":"Collecting Duct Pro(Renin) Receptor Contributes to Unilateral Ureteral Obstruction-Induced Kidney Injury via Activation of the Intrarenal RAS.","authors":"Renfei Luo, Kevin T Yang, Fei Wang, Huaqing Zheng, Tianxin Yang","doi":"10.1161/HYPERTENSIONAHA.123.21740","DOIUrl":"10.1161/HYPERTENSIONAHA.123.21740","url":null,"abstract":"<p><strong>Background: </strong>Although the concept of the intrarenal renin-angiotensin system (RAS) in renal disease is well-described in the literature, the precise pathogenic role and mechanism of this local system have not been directly assessed in the absence of confounding influence from the systemic RAS. The present study used novel mouse models of collecting duct (CD)-specific deletion of (pro)renin receptor (PRR) or renin together with pharmacological inhibition of soluble PRR production to unravel the precise contribution of the intrarenal RAS to renal injury induced by unilateral ureteral obstruction.</p><p><strong>Methods: </strong>We examined the impact of CD-specific deletion of PRR, CD-specific deletion of renin, and S1P (site-1 protease) inhibitor PF429242 treatment on renal fibrosis and inflammation and the indices of the intrarenal RAS in a mouse model of unilateral ureteral obstruction.</p><p><strong>Results: </strong>After 3 days of unilateral ureteral obstruction, the indices of the intrarenal RAS including the renal medullary renin content, activity and mRNA expression, and Ang (angiotensin) II content in obstructed kidneys of floxed mice were all increased. That effect was reversed with CD-specific deletion of PRR, CD-specific deletion of renin, and PF429242 treatment, accompanied by consistent improvement in renal fibrosis and inflammation. On the other hand, renal cortical renin levels were unaffected by unilateral ureteral obstruction, irrespective of the genotype. Similar results were obtained via pharmacological inhibition of S1P, the key protease for the generation of soluble PRR.</p><p><strong>Conclusions: </strong>Our results reveal that PRR-dependent/soluble PRR-dependent activation of CD renin represents a key determinant of the intrarenal RAS and, thus, obstruction-induced renal inflammation and fibrosis.</p>","PeriodicalId":13042,"journal":{"name":"Hypertension","volume":" ","pages":"2152-2161"},"PeriodicalIF":6.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11410543/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142017287","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":"Age-Related Blood Pressure Gradients Are Associated With Blood Pressure Control and Global Population Outcomes.","authors":"Janis M Nolde, Thomas Beaney, Revathy Carnagarin, George S Stergiou, Neil R Poulter, Aletta E Schutte, Markus P Schlaich","doi":"10.1161/HYPERTENSIONAHA.124.23406","DOIUrl":"10.1161/HYPERTENSIONAHA.124.23406","url":null,"abstract":"<p><strong>Background: </strong>The strong relationship between blood pressure (BP) and age is well known. Limited evidence suggests that a steeper age-BP slope may be associated with an increased risk of adverse outcomes. The May Measurement Month campaign enables an investigation of geographic, socioeconomic, and sex differences in age-related BP gradients and their association with public-health outcomes.</p><p><strong>Methods: </strong>Cross-sectional, annual global BP May Measurement Month screening data were analyzed. Average systolic BP and age-related BP slopes across different age groups were calculated to assess regional, socioeconomic, and sex-stratified variations. The association of BP slopes derived from adjusted linear regression models with country-level health metrics was investigated.</p><p><strong>Results: </strong>Age-related systolic BP gradients differed distinctly across global geographic regions, income levels, and between sexes. The steepest age gradients of BP were observed in populations from Africa and Europe. Women had lower BP levels than men at younger ages (20s and 30s) but subsequently experienced more pronounced age-related BP gradients. Geographically divergent age-related BP gradients were significantly associated with major national public health indicators. Globally, steeper age-related BP slopes were associated with poor BP control, increased disability-adjusted life years, and death rates. A steeper population age-BP slope of 1 mm Hg per 10 years was associated with a decrease in life expectancy of 3.3 years in this population (95% CI, -5.1 to -1.4; <i>P</i>=0.0007).</p><p><strong>Conclusions: </strong>Age-related BP gradients vary considerably across global populations and are associated with variability in BP-related risks and adverse outcomes across regions. Effective public health strategies may require region-specific targeting of adverse BP gradients to improve health outcomes.</p>","PeriodicalId":13042,"journal":{"name":"Hypertension","volume":" ","pages":"2091-2100"},"PeriodicalIF":6.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141897319","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":"Novel Drp1 GTPase Inhibitor, Drpitor1a: Efficacy in Pulmonary Hypertension.","authors":"Danchen Wu, Ross D Jansen-van Vuuren, Asish Dasgupta, Ruaa Al-Qazazi, Kuang-Hueih Chen, Ashley Y Martin, Jeffrey D Mewburn, Elahe Alizadeh, Patricia D A Lima, Oliver Jones, Pierce Colpman, Rachel E T Bentley, M Martin VandenBroek, Nolan M Breault, Isaac M Emon, V Siddartha Yerramilli, Luka Jedlovčnik, Yuan Yuan Zhao, Michael Wells, Gopinath Sutendra, Mark L Ormiston, Stephen L Archer","doi":"10.1161/HYPERTENSIONAHA.124.22822","DOIUrl":"10.1161/HYPERTENSIONAHA.124.22822","url":null,"abstract":"<p><strong>Background: </strong>Drp1 (dynamin-related protein 1), a large GTPase, mediates the increased mitochondrial fission, which contributes to hyperproliferation of pulmonary artery smooth muscle cells in pulmonary arterial hypertension (PAH). We developed a potent Drp1 GTPase inhibitor, Drpitor1a, but its specificity, pharmacokinetics, and efficacy in PAH are unknown.</p><p><strong>Methods: </strong>Drpitor1a's ability to inhibit recombinant and endogenous Drp1 GTPase was assessed. Drpitor1a's effects on fission were studied in control and PAH human pulmonary artery smooth muscle cells (hPASMC) and blood outgrowth endothelial cells (BOEC). Cell proliferation and apoptosis were studied in hPASMC. Pharmacokinetics and tissue concentrations were measured following intravenous and oral drug administration. Drpitor1a's efficacy in regressing monocrotaline-PAH was assessed in rats. In a pilot study, Drpitor1a reduced PA remodeling only in females. Subsequently, we compared Drpitor1a to vehicles in control and monocrotaline-PAH females.</p><p><strong>Results: </strong>Drp1 GTPase activity was increased in PAH hPASMC. Drpitor1a inhibited the GTPase activity of recombinant and endogenous Drp1 and reversed the increased fission, seen in PAH hPASMC and PAH BOEC. Drpitor1a inhibited proliferation and induced apoptosis in PAH hPASMC without affecting electron transport chain activity, respiration, fission/fusion mediator expression, or mitochondrial Drp1 translocation. Drpitor1a did not inhibit proliferation or alter mitochondrial dynamics in normal hPASMC. Drpitor1a regressed monocrotaline-PAH without systemic vascular effects or toxicity.</p><p><strong>Conclusions: </strong>Drpitor1a is a specific Drp1 GTPase inhibitor that reduces mitochondrial fission in PAH hPASMC and PAH BOEC. Drpitor1a reduces proliferation and induces apoptosis in PAH hPASMC and regresses monocrotaline-PAH. Drp1 is a therapeutic target in PAH, and Drpitor1a is a potential therapy with an interesting therapeutic sexual dimorphism.</p>","PeriodicalId":13042,"journal":{"name":"Hypertension","volume":" ","pages":"2189-2201"},"PeriodicalIF":6.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11410511/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142004115","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}