Hypertension最新文献

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

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.

Background: 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.

Methods: We developed clinically relevant models that mimic gender-affirming hormone therapy combination therapies utilized for the endocrine treatment of gender dysphoria in transgender women.

Results: 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.

Conclusions: 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.

Background: Hypertension is the most common chronic disease and a major modifiable risk factor for cardio-cerebrovascular and renal diseases. This study estimated the national burden of hypertension, defined as systolic blood pressure ≥140 mm Hg, on morbidity and mortality in 2021 in France.

Methods: For all diseases causally associated with hypertension (cardiovascular diseases, chronic kidney diseases, and dementia), the number and proportion of cases attributable to hypertension in adults aged ≥35 years were estimated using population attributable fractions. Age- and sex-specific population attributable fractions were computed using the distribution of hypertension in the French population. These population attributable fractions were applied to nationwide statistics for mortality, hospitalizations, disease prevalence, years of life lost, years of life lived with disability, and disability-adjusted years of life.

Results: The largest population attributable fractions were for ischemic heart disease and hemorrhagic stroke, with over 40% of cases attributable to hypertension. Overall, more than 385 000 patients were hospitalized due to hypertension, with 3.7 million hospitalizations and 6.2 million hospital days (all hospitalizations, including 3.4 million for chronic kidney disease) and including 390 000 overnight hospitalization. In 2021, more than 1.15 million individuals lived with ischemic heart disease attributable to hypertension, 1.26 million with chronic kidney diseases, and 358 033 with heart failure. Among 184 059 annual deaths from cardiovascular diseases, dementia, and chronic kidney diseases, 30% (55 280 deaths) were attributable to hypertension. Hypertension accounted for 8.5% of all deaths and 498 052 years of life lost.

Conclusions: In France, despite near-universal health coverage and free health care access, the burden attributable to hypertension remains high.

Background: The importance of the brain renin-angiotensin system in cardiovascular function is well accepted. However, not knowing the precise source of renin in the brain has been a limitation toward a complete understanding of how the brain renin-angiotensin system operates.

Methods: Highly sensitive in situ hybridization techniques and conditional knockout mice were used to address the location and function of renin in the brainstem.

Results: We identified novel renin-expressing cholinergic neurons in the nucleus ambiguus (NuAm), a major vagal cardioinhibitory center in the brainstem. The expression of renin-angiotensin system genes was relatively abundant in the NuAm, implying that angiotensin II might mediate an important regulatory role in this nucleus and other regions with neural connectivity to the NuAm. Then, we generated conditional knockout mice lacking the classical renin isoform (Ren-a^ChAT-KO), specifically in cholinergic neurons. Ablation of Ren-a in cholinergic neurons abrogated renin expression in the NuAm. Moreover, studies using radiotelemetry, heart rate variability analyses, and pharmacological approaches revealed that the parasympathetic nervous system is depressed in Ren-a^ChAT-KO males while augmented in the Ren-a^ChAT-KO females. Subsequently, transcriptomic approaches were used to infer putative genes and signaling pathways regulated by renin within the NuAm.

Conclusions: This study revealed that renin in cholinergic neurons plays a fundamental role in preserving autonomic balance and cardiovascular homeostasis in a sex-dependent manner. These findings define the NuAm as an endogenous, local source of renin with biological function and serve as conclusive evidence for the presence and functionality of the brain renin-angiotensin system.

Several microRNAs (miRNAs) strongly influence blood pressure and the development of hypertension by modulating vascular, renal, and other physiological mechanisms. In addition, miRNAs may contribute to the genetic regulation of blood pressure. Future research should focus on investigating select miRNAs with potent physiological effects, understanding cellular context-dependent mechanisms conferring specificity to miRNA action, and integrating miRNAs as powerful modulators into the molecular system that underlies the regulation of blood pressure and the development of hypertension.

Background: Renin-independent aldosterone production in normotensive people increases risk for developing hypertension. In parallel, normotensive adrenal glands frequently harbor aldosterone-producing micronodules with pathogenic somatic mutations known to induce primary aldosteronism (PA). A deeper understanding of these phenomena would inform the origins of PA and its role in hypertension pathogenesis.

Methods: Prospectively recruited normotensives underwent detailed characterization of PA features via the following: oral sodium suppression test to evaluate renin-independent aldosterone production, dexamethasone suppression and adrenocorticotropic hormone-stimulation tests to evaluate adrenocorticotropic hormone-mediated aldosterone production, and 24-hour ambulatory blood pressure monitoring. The magnitude of renin-independent aldosterone production was defined via tertiles of 24-hour urinary aldosterone production during the oral sodium suppression test to create unbiased categorizations of the magnitude of PA. Serum aldosterone, serum 18-hybrid steroids, urine tetrahydroaldosterone (biomarkers of aldosterone synthase activity), urinary potassium, and blood pressure (biomarkers of mineralocorticoid receptor activation) were evaluated across tertiles.

Results: There was a spectrum of autonomous, nonsuppressible, and renin-independent production of aldosterone, 18-hybrid steroids, and 24-hour urinary tetrahydroaldosterone (P-trend <0.01). Correspondingly, there was a continuum of adrenocorticotropic hormone-mediated aldosterone production and 18-hybrid steroid production that also paralleled renin-independent aldosterone production. The spectrum of PA pathophysiology was associated with higher ambulatory daytime systolic BP (P-trend <0.05), even within the normotensive range, and greater urinary potassium excretion (P-trend <0.05), indicating a continuum of mineralocorticoid receptor activation.

Conclusions: The pathophysiologic continuum of PA, characterized by renin-independent and adrenocorticotropic hormone-mediated aldosterone production, and enhanced aldosterone synthase and mineralocorticoid receptor activity, is evident in normotensive people. These findings provide mechanistic explanations to implicate PA in the pathogenesis of a substantial proportion of hypertension.

Background: To understand the role of hypertensive disorders of pregnancy (HDP), including preeclampsia and gestational hypertension (GH), in brain health earlier in life, we investigated the association of HDP with midlife cognition and brain health.

Methods: We studied a prospective cohort of women, baseline age 18 to 30 years, who were assessed at study years 25 and 30 with a cognitive battery and a subset with brain magnetic resonance imaging. A history of HDP was defined based on self-report. We conducted linear regression to assess the association of a history of preeclampsia, GH, or no HDP with cognition and brain magnetic resonance imaging white matter hyperintensities.

Results: Among 1441 women (mean age, 55.2±3.6 years), 202 reported preeclampsia and 112 reported GH. GH was associated with worse cognitive performance: global cognition (mean score, 23.2 versus 24.0; P=0.018), processing speed (67.5 versus 71.3; P=0.01), verbal fluency (29.5 versus 31.1; P=0.033), and a trend for executive function (24.3 versus 22.6; P=0.09), after multivariable adjustment. GH was associated with a greater 5-year decline in processing speed (mean change, -4.9 versus -2.7; P=0.049) and executive function (-1.7 versus 0.3; P=0.047); preeclampsia was associated with a greater 5-year decline on delayed verbal memory (-0.3 versus 0.1; P=0.041). GH and preeclampsia were associated with greater white matter hyperintensities in the parietal and frontal lobes, respectively.

Conclusions: GH and preeclampsia are associated with cognition and white matter hyperintensities during midlife, with differences in cognitive domains and brain lobes. Women with HDP may need to be closely monitored for adverse brain outcomes starting in midlife.

Background: Epigenetic changes can be shaped by a wide array of environmental cues, maternal health, and behaviors. One of the most detrimental behaviors to the developing fetus is nicotine exposure. Perinatal nicotine exposure remains a significant risk factor for cardiovascular health and, in particular, hypertension. Increased basal carotid body (CB) activity and excitation are significant contributors to hypertension. This study investigated the epigenetic changes to CB activity induced by perinatal nicotine exposure resulting in CB-mediated hypertension.

Methods: We used a rodent model of perinatal nicotine exposure and cell culture methods.

Results: We show that the AgtR1 (angiotensin II type 1 receptor) is upregulated in the carotid bodies of nicotine-exposed offspring. These changes were attributed to an upregulation of genetic promotion as DNA methylation of AgtR1 occurred within intron regions, exemplifying an upregulation of genetic transcription for this gene. Nicotine increased angiotensin signaling in vitro. CB reactivity to angiotensin was increased in perinatal nicotine-exposed offspring compared with control offspring. Furthermore, CB denervation reduced arterial pressure because of suppressed efferent sympathetic activity in perinatal nicotine-exposed offspring.

Conclusions: Our data demonstrate that perinatal nicotine exposure adversely affects CB afferent sensing, which augments efferent sympathetic activity to increase vasoconstrictor signaling and induce hypertension. Targeting angiotensin signaling in the carotid bodies may provide a way to alleviate hypertension acquired by adverse maternal uterine environments in general and perinatal nicotine exposure in particular.

Background: Dietary Approaches to Stop Hypertension (DASH) is a recommended first-line treatment for adults with hypertension, yet adherence to DASH is low. To evaluate the efficacy of a digital health intervention (DHI), compared with attention control, on changes in DASH adherence and blood pressure among adults with hypertension.

Methods: Nourish was a 12-month, parallel, 2-arm, randomized controlled trial of a virtually delivered DHI. Participants had a previous diagnosis of hypertension. The primary outcome was a 6-month change in DASH adherence. The secondary outcome was a change in blood pressure. We used linear mixed models to compare 6 and 12-month changes in DASH adherence, systolic blood pressure, and diastolic blood pressure.

Results: Nourish randomized 301 adults who averaged 54.4 (SD, 13.4) years and predominately identified as female (65%), White (53%), or Black (31%). Adjusted mean baseline DASH score was 2.30 (95% CI, 2.03-2.58). The adjusted mean baseline systolic blood pressure and diastolic blood pressure were 123.2 (95% CI, 119.5-126.9) and 77.1 (95% CI, 74.6-79.6) mm Hg. DASH score change was not significantly different between arms at 6 months (M_diff, 0.02 [95% CI, -0.37 to 0.40]). Yet, DHI participants had significantly greater 12-month changes in DASH score, relative to control (M_diff, 0.62 [95% CI, 0.16-1.08]). Between-group differences in 6-month changes were insignificant for systolic blood pressure and marginally significant for diastolic blood pressure, despite the DHI group showing significant blood pressure reductions from baseline.

Conclusions: A DHI led to modest improvements in DASH and blood pressure among adults with hypertension but did not outperform the attention control. Further research is needed to understand the utility of DHIs to promote DASH and identify intervention components that support long-term behavior change.