Hypertension最新文献

Background: Cardiomyocyte oxidative stress significantly contributes to the progression of hypertension-induced heart failure, highlighting the need for targeted therapies. We developed a novel peptide, NPA7, that coactivates the GC-A (guanylyl cyclase A)/cGMP and MasR (Mas receptor)/cAMP pathway. This study aimed to test NPA7's ability to inhibit oxidative stress by modulating the p62 (Sequestosome 1)-KEAP1 (Kelch-like ECH-associated protein 1)-NRF2 (nuclear factor erythroid 2-related factor 2) pathway in human cardiomyocytes (HCMs) and a rat model of hypertension.

Methods: Oxidative stress was induced in HCMs using H₂O₂ with phosphate-buffered saline or NPA7 treatment. Intracellular reactive oxygen species levels were assessed via dihydroethidium staining. Western blotting analysis measured p62, KEAP1, and NRF2 protein levels, while GSH/GSSG (glutathione/glutathione disulfide) ratios and antioxidant gene expression were analyzed. HCMs were transfected with small interfering RNA targeting GC-A, MasR, or p62 before NPA7 and H₂O₂ treatment. In vivo, spontaneously hypertensive rats received saline or NPA7, with normotensive Wistar Kyoto rats as control and cardiac oxidative stress, KEAP1 protein levels, NOX2 (NADPH oxidase 2), and p67 (NADPH oxidase subunit p67-phox) mRNA levels were measured.

Results: NPA7 reduced H₂O₂-induced reactive oxygen species levels and increased GSH/GSSG ratio in HCMs. Silencing GC-A (guanylyl cyclase A receptor) and MasR (Mas receptor) reversed NPA7's effects. NPA7 activated the KEAP1-NRF2 pathway, enhancing NRF2's antioxidant target gene expression. In p62 knockdown HCMs, NPA7-induced KEAP1 degradation and NRF2 activation were diminished. Reactive oxygen species levels were elevated in spontaneously hypertensive rat versusWistar Kyoto rats' hearts, however, NPA7 treatment reduced myocardial reactive oxygen species, suppressed KEAP1 protein, and decreased NOX2 and p67 mRNA levels.

Conclusions: NPA7 exhibits antioxidant properties in HCMs and spontaneously hypertensive rat hearts by targeting GC-A and MasR through the p62-KEAP1-NRF2 pathway, supporting a novel therapeutic approach against cardiovascular disease-related oxidative stress.

Background: The infiltration of macrophages into the lungs is a common characteristic of perivascular inflammation, contributing to vascular remodeling in pulmonary hypertension (PH). Peli1 (pellino E3 ubiquitin-protein ligase 1) plays a critical role in regulating the production of proinflammatory cytokines and the polarization of macrophages in various diseases. However, the role of Peli1 in PH remains to be investigated.

Methods: The expression and biological function of Peli1 were investigated in both human and experimental models of PH. Peli1-deficient mice and bone marrow transplant mice were utilized to explore the roles of Peli1 in macrophages in vivo. Proteomic analysis and molecular biology techniques were used to uncover the underlying mechanisms.

Results: The upregulation of Peli1 in the lungs and alveolar macrophages was observed in hypoxia-treated mice. Peli1 knockout mice and myeloid Peli1-deficient mice significantly ameliorated hypoxia-induced right ventricular systolic pressure, right ventricular hypertrophy, and pulmonary vascular remodeling. Mechanistically, Peli1 facilitated the ubiquitination and subsequent proteasomal degradation of Foxp1 (forkhead box p1), thereby alleviating its suppression of IL (interleukin)-6 transcription and contributing to macrophage activation. Furthermore, myeloid Foxp1 deficiency partially eliminates the protective effect of myeloid Peli1 deficiency in hypoxia-induced PH mice.

Conclusions: Our findings demonstrate that the Peli1-Foxp1-IL-6 pathway plays a crucial role in macrophage activation and recruitment during the development of PH, underscoring the potential of Peli1 as a therapeutic target for PH.

In 2024, the European Society of Cardiology released a new guideline for the management of elevated blood pressure (BP) and hypertension. The guideline introduced a new BP categorization: (1) nonelevated (office BP <120/70 mm Hg) for which drug treatment is not recommended, (2) elevated (120-139/70-89 mm Hg) for which drug treatment is recommended based on cardiovascular disease risk and follow-up BP level, and (3) hypertension (≥140/90 mm Hg) for which prompt confirmation and drug treatment are recommended in most individuals. The initial default systolic BP treatment target is 120 to 129 mm Hg; however, relaxed targets (BP as low as reasonably achievable) are recommended in case of treatment intolerance, adults ≥85 years, symptomatic orthostasis, moderate-to-severe frailty, or limited life expectancy. Here, we summarize what is new and different in the 2024 European Society of Cardiology guidelines, relative to other major international hypertension guidelines in Europe and America. Our aim is to reconcile any uncertainty clinicians may have about implementing these various guidelines in patient care.

Background: Hypertension in adolescence is associated with subclinical target organ injury. We aimed to determine whether different blood pressure thresholds were associated with an increasing number of target organ injury markers in healthy adolescents.

Methods: A total of 244 participants (mean age 15.5±1.8 years, 60.1% male) were studied. Participants were divided based on systolic clinic and systolic awake ambulatory blood pressure into low- (<75th percentile), mid- (75th-90th percentile), and high-risk (>90th percentile) groups. The ambulatory blood pressure phenotype was classified as normotensive, white-coat, masked, or sustained hypertension. Target organ injury assessments included left ventricular mass, systolic and diastolic function, and vascular stiffness. A multivariable general linear model was constructed to evaluate the association of different participant characteristics with higher numbers of target organ injury markers.

Results: A total of 31.2% of participants had 1, 11.9% 2, 3.7% 3, and 0.8% 4 target organ injury markers. The number of target organ injury markers increased according to the risk groups: the percentage of participants with >1 marker in the low-, mid-, and high-risk groups was 6.7%, 19.1%, and 21.8% (P=0.02) and 9.6%, 15.8%, and 32.2% (P<0.001), based on clinic and ambulatory blood pressure, respectively. Participants with white-coat (23%), masked (35%), and sustained hypertension (32%) had significantly higher >1 target organ injury marker than normotensives (8%, P<0.001). The results were unchanged in multivariate analysis.

Conclusions: High clinic and ambulatory blood pressure values, as well as ambulatory blood pressure phenotypes (white-coat, masked, and sustained hypertension), were independently associated with an increasing number of subclinical cardiovascular injury markers in adolescents.

Background: The impact of preventing hypertension and maintaining normal blood pressure (BP) on life expectancy and healthy life expectancy (HLE) among Black adults, who are disproportionately affected by hypertension, has not been quantified.

Methods: We used a discrete event simulation to estimate life expectancy and HLE among a cohort of Black adults from the Jackson Heart Study (n=4933) from age 20 to 100 years or until death. We modeled preventing hypertension as having BP <130/80 mm Hg and maintaining normal BP as having BP <120/80 mm Hg across the lifespan. In the primary analysis, we assumed that lowering BP decreased the risk of cardiovascular disease events, resulting in life expectancy and HLE gains. In a secondary analysis, we assumed that preventing hypertension and maintaining normal BP directly reduced both cardiovascular disease and mortality risk.

Results: At age 20 years, the projected average life expectancy was age 80.8 (95% uncertainty interval [UI], 80.6-81.1) years, and HLE was 70.5 (95% UI, 70.3-70.7) healthy life years. In the primary analysis, preventing hypertension and maintaining normal BP added 0.9 (95% UI, 0.8-1.1) and 1.1 (95% UI, 0.9-1.3) years to life expectancy, respectively, and 2.7 (95% UI, 2.6-2.9) and 2.9 (95% UI, 2.7-3.1) healthy life years to HLE, respectively. In the secondary analysis, preventing hypertension and maintaining normal BP added 4.5 (95% UI, 4.3-4.6) and 4.6 (95% UI, 4.4-4.8) years to life expectancy, respectively, and 5.7 (95% UI, 5.6-5.8) and 5.9 (95% UI, 5.7-6.0) healthy life years to HLE, respectively.

Conclusions: Preventing hypertension and maintaining normal BP were projected to increase life expectancy and HLE among Black adults.

Background: Primary aldosteronism, an endocrinopathy present in ≥10% to 25% of patients with hypertension, confers excess cardiovascular risk that can be mitigated with aldosterone-directed therapy. However, only 2% of eligible patients undergo guideline-recommended screening. This study aimed to bypass clinical inertia and identify people with primary aldosteronism using pragmatic, direct-to-patient testing.

Methods: Hypertensive adults were recruited via online platforms and underwent virtual consent and local phlebotomy. Using a standardized diagnostic algorithm, laboratory results with interpretations were communicated to patients and primary care providers. Follow-up was ascertained at 6 to 12 months. The primary outcome was the frequency of a positive test for primary aldosteronism. Secondary outcomes included follow-up primary aldosteronism testing and implementation of aldosterone-targeted therapies.

Results: The study population (N=694) had a mean age of 63.3±11.3 years, was 52.2% female, and hailed from 41 US states. Overall, 25.4% had a positive test for primary aldosteronism. Sleep apnea, resistant hypertension, and hypokalemia were the most common testing indications, with 55.2% of participants having ≥2 indications. Over half of participants (57%) were already under endocrinology, cardiology, or nephrology care, yet had not been tested. In longitudinal follow-up of participants with a positive result, 25.5% had additional testing and 13.7% were started on aldosterone-targeted therapy (mineralocorticoid receptor antagonist or adrenalectomy).

Conclusions: Pragmatic, direct-to-patient testing, and simplified results interpretation is a feasible, scalable method to increase primary aldosteronism diagnoses and implementation of aldosterone-targeted therapies. Given that new hypertension guidelines recommend primary aldosteronism screening in all hypertensive people, practical approaches to test, interpret, and implement results will be essential.