Hypertension最新文献

Background: Transcatheter renal denervation (RDN) remains inconsistent despite developments in ablation technologies, due to the lack of an intraprocedural physiological end point. The aim of this study was to identify if aorticorenal ganglion (ARG) guided RDN using microwave (MW) catheter leads to more consistent denervation outcomes compared with empirical MW ablation.

Methods: Pigs underwent sham procedure (n=8) or bilateral RDN using an in-house built open-irrigated MW catheter. Before denervation, ipsilateral ARG pacing was performed leading to renal artery vasoconstriction. MW ablation group (MW-group; n=7) received 1 ablation (100-120 W for 360 seconds) in the mid-main renal artery based on artery caliber. ARG-guided-MW ablation group (ARG-MW-group; n=7) was permitted an additional ablation more distally or at higher power until a vasoconstrictive response was abolished. Animals were euthanized at 4 to 5 weeks post-procedure.

Results: ARG pacing caused an ipsilateral reduction in renal artery caliber from 4.67 to 4 mm; P=0.0006 in MW-group and 4.8 to 3.9 mm; P=0.001 in ARG-MW-group. Repeat ARG pacing at euthanasia led to a reduction in renal artery caliber in MW-group from 5.1 to 4.8 mm; P=0.006, but not in ARG-MW-group from 4.88 to 4.55 mm; P=0.08. There were no differences in ablation injury volumes between the groups. Compared with undenervated sham controls, ARG-MW-RDN versus MW-RDN caused median reductions in viable nerve area (antityrosine hydroxylase staining) at 4 to 5 weeks by 92.6% (interquartile range, 0.94-19.59%; P<0.0001) versus 55.02% (interquartile range, 15.87-75.11%; P=0.006) and median renal cortical norepinephrine content by 68.06% (interquartile range, 27.16-38.39%; P<0.0001) versus 25.25% (interquartile range, 56.97-157.7%; P=NS).

Conclusions: ARG pacing serves as a physiological procedural end point to guide MW denervation to improve denervation outcomes.

Background: The long-term associations between metal mixtures in pregnancy and women's mid-life blood pressure (BP) and hypertension remain unclear.

Methods: In Project Viva (enrolled 1999-2002), we measured nonessential (arsenic, barium, cadmium, cesium, mercury, lead) and essential metals (copper, magnesium, manganese, selenium, zinc) in red blood cells, along with folate and vitamin B12 in plasma, collected during pregnancy. We measured mid-life BP from 2017 to 2021 (median age, 51.2 years). We examined associations of individual metals with BP using linear regression and with hypertension (≥130/80 mm Hg or use of antihypertensive medication) using modified Poisson regression. We used Bayesian kernel machine regression to examine the mixture effects of metals and micronutrients.

Results: The median follow-up time of the 493 women was 18.1 years (interquartile range, 17.8-18.6 years). After adjustment, a doubling of copper and manganese was associated with 0.75 (95% CI, 0.57-0.99) and 0.80 (95% CI, 0.71-0.91) times the risk of hypertension, respectively. Although higher cesium and selenium levels were associated with a slightly increased risk of hypertension, the 95% CIs were wide and crossed the null. A doubling of vitamin B12 was associated with a 3.64 (95% CI, 1.23-6.04) mm Hg lower systolic BP and a 2.52 (95% CI, 0.72-4.32) mm Hg lower diastolic BP. Bayesian kernel machine regression showed linear associations with no metal-metal or metal-micronutrient interactions. The essential metal mixture was monotonically associated with lower BP, while its association with hypertension showed threshold effects.

Conclusions: Optimizing essential metal levels during pregnancy, particularly copper and manganese, along with vitamin B12, may protect against higher BP and hypertension in mid-life women.

Background: Black individuals frequently present with resistant hypertension and disproportionately increased cardiovascular risk. We investigated the blood pressure (BP)-lowering effect of the dual endothelin receptor antagonist aprocitentan in Black individuals enrolled in the PRECISION study (Parallel-Group, Phase 3 Study with Aprocitentan in Subjects with Resistant Hypertension).

Methods: Patients with confirmed resistant hypertension were randomized to aprocitentan 12.5 mg, 25 mg, or placebo for 4 weeks (part 1). They subsequently received aprocitentan 25 mg for 32 weeks (part 2) before re-randomization to aprocitentan 25 mg or placebo (part 3).

Results: Eighty-two patients randomized in the PRECISION study were Black individuals. At week 4, aprocitentan 12.5 and 25 mg reduced office trough systolic BP (-11.3 and -11.9 mm Hg) to a similar degree as placebo (-12.0 mm Hg). Using 24-hour ambulatory BP monitoring, the placebo effect was minimal (-0.7 mm Hg), and aprocitentan reduced systolic BP by 4.0 and 8.6 mm Hg. During part 2, office BP continued to decrease (-16.4 mm Hg at week 36). In part 3, office and ambulatory systolic BP increased on placebo (+9.9 and +8.1 mm Hg, respectively), whereas the BP-lowering effect was maintained with aprocitentan. Aprocitentan markedly reduced albuminuria during the study. The most frequent adverse event was peripheral edema, occurring in 3 patients (10%) receiving aprocitentan 25 mg versus none receiving aprocitentan 12.5 mg or placebo.

Conclusions: Aprocitentan reduced BP and albuminuria in Black individuals with resistant hypertension. The BP-lowering efficacy was similar to that of the overall PRECISION population. Aprocitentan may represent an important addition to the often difficult-to-control hypertension in Black individuals.

Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03541174.

Background: Hypertension is a major global health issue. Aldosterone synthase inhibitors (ASIs) have emerged as a promising therapeutic strategy for blood pressure control.

Methods: A thorough search of the MEDLINE and Embase databases up to March 30, 2024, identified randomized trials comparing ASIs with a placebo for hypertension treatment. Data extraction was done independently by 2 authors. Both random-effects (Restricted maximum likelihood) and fixed-effects meta-analyses were conducted to account for diversity and study size, respectively. Risk ratios for binary outcomes and mean differences for continuous outcomes were calculated.

Results: Seven randomized controlled trials involving 1440 patients (mean age, 60 years; 39% women) were included. The analysis showed that ASIs reduced office systolic blood pressure by 6.3 mm Hg ([95% CI, -8.8 to -3.8]; P<0.0001) and diastolic blood pressure by 2.2 mm Hg ([95% CI, -4.2 to -0.2]; P=0.03). The risk ratio for adverse events was 1.1 ([95% CI, 0.9-1.2]; P=0.3), with a similar trend for serious adverse events (risk ratio, 1.0 [95% CI, 0.5-2.3]; P=0.95). No treatment-related deaths occurred. However, the risk of hyperkalemia was higher with ASIs (risk ratio, 2.5 [95% CI, [1.2-5.4]; P<0.02).

Conclusions: ASIs effectively reduce systolic and diastolic blood pressure in hypertensive patients and have a tolerable safety profile. The increased risk of hyperkalemia requires careful monitoring. These findings suggest ASIs are a potential treatment option for hypertension, pending further research in larger studies.

Background: 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.

Methods: Single-nucleotide polymorphisms in HMGCR, NPC1L1, and PCSK9 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.

Results: Genetically proxied inhibition of HMGCR was negatively associated with systolic BP (β, -0.81 [95% CI, -1.26 to -0.37 mm Hg]; P=3.72×10^-4) and diastolic BP (β, -1.58 [95% CI, -2.24 to -0.91 mm Hg]; P=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]; P=4.25×10^-8). However, there was no association of PCSK9 and NPC1L1 inhibition with BP or fasting glucose.

Conclusions: 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.

Background: Exposure to cold environments is linked to cold-induced hypertension due to activated sympathetic nerve activity (SNA) and arterial baroreceptor reflex dysfunction. However, direct measurement of SNA during cold-induced hypertension and changes in baroreflex control of SNA remain unexplored.

Methods: Chronically instrumented rats were exposed to cold temperatures (10 °C) over 4 days after a control period (24 °C), and renal and lumbar sympathetic nerve activities were simultaneously measured during cold-induced hypertension. Baroreflex curves for renal SNA (RSNA) and lumbar SNA and heart rate were generated by altering arterial pressure via a bolus intravenous infusion of vasoactive drugs.

Results: RSNA increased immediately after cold exposure, increased progressively throughout the 4-day period, and remained high after the cold exposure ended. Cold exposure shifted the RSNA baroreflex curve to the right and upward, gradually increasing the upper plateau (maximum capacity of sympathetic drive). The upper plateau remained elevated even after the cold exposure ended. Conversely, cold exposure increased lumbar SNA, heart rate, and arterial pressure, which subsequently returned to control levels after the cold exposure ended. These data indicate that cold exposure increases the maximum capacity to drive renal SNA in a regionally different and time-dependent manner through cumulative effects.

Conclusions: Four days of cold exposure resulted in reversible effects increasing arterial pressure via lumbar SNA and heart rate, alongside time-dependent cumulative effects on RSNA. This study provides direct evidence of a self-activating pathway for RSNA that is activated by cold exposure, thus initiating cold-induced hypertension.

Background: 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.

Methods: 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 clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9-generated knock-in mouse model to elucidate the mechanism underlying hypertension-induced TAAD.

Results: The KCNJ5 p.R242Q 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 KCNJ5 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.

Conclusions: Familial TAAD may stem from KCNJ5 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.

Background: The mediating role of inflammatory biomarkers in the causal relationship between body composition and hypertension remains unclear and requires further investigation.

Methods: This study used a combination of retrospective observational analysis and Mendelian randomization approaches. Observational data were derived from 4717 Chinese children and adolescents aged 6 to 18 years who underwent dual-energy X-ray absorptiometry to assess body composition. Mendelian randomization analyses utilized summary statistics from large-scale data sets, including UK Biobank, deCODE2021, International Consortium of Blood Pressure, FinnGen, and other consortia. The inflammatory biomarkers included leptin, insulin, adiponectin, osteocalcin, FGF23 (fibroblast growth factor 23), and PTH (parathyroid hormone).

Results: The observational analysis revealed that increased fat mass positively influenced diastolic blood pressure through osteocalcin, while fat-free mass had an inverse effect. Insulin mediated the association between fat mass and systolic blood pressure, diastolic blood pressure, and hypertension, with additional indirect effects observed for PTH (all P<0.05). The Mendelian randomization analyses demonstrated a causal relationship between childhood body mass index and hypertension mediated by insulin (indirect effect: odds ratio, 0.87 [95% CI, 0.78-0.97]) and adiponectin (odds ratio, 1.13 [95% CI, 1.04-1.23]). Adiponectin mediated the effects of fat-free mass (odds ratio, 0.81 [95% CI, 0.71-0.93]) and fat mass (odds ratio, 1.30 [95% CI, 1.11-1.51]) on hypertension. Leptin, adiponectin, and insulin also mediated the causal effects of body composition on systolic blood pressure, diastolic blood pressure, and hypertension.

Conclusions: These findings indicate that body composition influences blood pressure through distinct inflammatory biomarkers. Targeting inflammatory biomarkers may provide tailored strategies for managing body composition and hypertension.