Hypertension during pregnancy and preeclampsia are associated with increased arterial thrombotic risk in later life. Whether these complications are associated with risk of venous thromboembolism (VTE) on the short term after pregnancy and on the long term, that is, outside pregnancy, is largely unknown. We conducted a nationwide cohort study in women with at least 1 pregnancy and their first VTE risk by linking the Dutch perinatal registry (Perined) to anticoagulation clinics. We used Cox proportional hazard models to estimate hazard ratios (HRs) and corresponding 95% CI for VTE risk in women with hypertension during pregnancy, women with preeclampsia, compared with women with uncomplicated pregnancies (reference). A total of 1 919 918 women were followed for a median of 13.7 (interquartile range, 7.6–19.2) years for a total of 24 531 118 person-years in which 5759 first VTEs occurred; incidence rate: 2.3 (95% CI, 2.3–2.4) per 10 000 person-years. In the first pregnancy and 3-month postpartum period, VTE risk was higher in women with hypertension, HR, 2.0 (95% CI, 1.7–2.4), and highest among women with preeclampsia, HR, 7.8 (95% CI, 5.4–11.3), versus the reference group. On the long term, women with hypertension during pregnancy and preeclampsia had a higher VTE risk: HR, 1.5 (95% CI, 1.4–1.6) and HR, 2.1 (95% CI, 1.8–2.4), respectively, versus the reference group. When excluding events during pregnancy and postpartum, these HRs were 1.4 (95% CI, 1.3–1.5) and 1.6 (95% CI, 1.4–2.0), respectively. In conclusion, hypertension during pregnancy and preeclampsia are associated with an increased VTE risk during pregnancy and postpartum period and in the 13 years after.

Plasma metabolic profiles were compared between patients with hypertension with and without left ventricular hypertrophy and significantly decreased oleic acid (OA) levels were observed in the peripheral blood of patients with hypertension with left ventricular hypertrophy. We sought to determine the effect and underlying mechanisms of OA on cardiac remodeling. In vitro studies with isolated neonatal mouse cardiomyocytes and cardiac fibroblasts revealed that OA significantly attenuated Ang II (angiotensin II)-induced cardiomyocyte growth and cardiac fibroblast collagen expression. In vivo, cardiac function, hypertrophic growth of cardiomyocytes, and fibrosis were analyzed after an Ang II (1000 ng/kg/minute) pump was implanted for 14 days. We found that OA could significantly prevent Ang II-induced cardiac remodeling in mice. RNA sequencing served as a gene expression roadmap highlighting gene expression changes in the hearts of Ang II-induced mice and OA-treated mice. The results revealed that FGF23 (fibroblast growth factor 23) expression was significantly upregulated in mouse hearts in response to Ang II infusion, which was significantly suppressed in the hearts of OA-treated mice. Furthermore, overexpression of FGF23 in the heart by injection of an AAV-9 vector aggravated Ang II-induced cardiac remodeling and impaired the protective effect of OA on cardiac remodeling. Further study found that OA could suppress Ang II-induced FGF23 expression by inhibiting the translocation of Nurr1 (nuclear receptor–related 1 protein) from the cytoplasm to the nucleus. Our findings suggest a novel role of OA in preventing Ang II-induced cardiac remodeling via suppression of FGF23 expression.

This study sought to analyze blood pressure trends in children with Down syndrome at multiple centers. A multicenter, retrospective, cross-sectional study was performed. All patients were <18 years and had a diagnosis of Down syndrome. Existing comorbidities were nonexclusionary. For each patient, 3 blood pressure recordings were obtained from routine clinic visits. In total, 887 patients with 2661 total blood pressure recordings were included in this study. The average blood pressure percentile for patients was 38.87 with a median percentile of 31.5. Age, sex, and race were not predictive of blood pressure percentile. Compared with established data from the National Heart Lung and Blood Institute and National Health and Nutrition Examination Survey cohort (ages 8–18 years), blood pressure in our Down syndrome population was statistically lower by 6.1 percentile points (P<0.001), with the greatest difference at higher blood pressure percentiles (P<0.001). Only 10% of all Down syndrome cohort blood pressure recordings were greater than the National Heart Lung and Blood Institute/National Health and Nutrition Examination Survey 70th percentile, with no patients meeting criteria for prehypertension or hypertension. Additional comparisons against American Academy of Pediatrics data were similar and statistically significant. In children with Down syndrome, there is a 12 percentile point reduction in baseline blood pressure compared with age- and height-matched controls reported in the National Heart Lung and Blood Institute/National Health and Nutrition Examination Survey and American Academy of Pediatrics cohorts. This data can potentially be utilized in the evaluation and care of persons with Down syndrome in their pediatric medical homes.

Limited data exist evaluating the effect of blood pressure (BP) on clinical outcomes among patients with acute ischemic stroke with large vessel occlusion treated with mechanical thrombectomy (MT). We sought to evaluate the association of BP levels on clinical outcomes among patients with acute ischemic stroke with large vessel occlusion treated with MT. Studies were identified that reported the association of systolic BP (SBP) or diastolic BP levels before, during, or after MT on the outcomes of patients with acute ischemic stroke treated with MT. Unadjusted and adjusted analyses of studies reporting odds ratios (ORadj) per 10 mm Hg BP increment were performed. Our analysis included 25 studies comprising 6474 patients. Higher pre-MT mean SBP (P=0.008) and post-MT maximum SBP (P=0.009) levels were observed in patients who died within 3 months. Patients with 3-month functional independence were noted to have lower pre-MT (P<0.001) and post-MT maximum SBP levels (P<0.001). In adjusted analyses, increasing post-MT maximum SBP and diastolic BP levels were associated with 3-month mortality (ORadj, 1.19 [95% CI,1.00–1.43]; I2=78%, P value for Cochran Q test: 0.001) and symptomatic intracranial hemorrhage (ORadj, 1.65 [95% CI, 1.11–2.44]; I2=0%, P value for Cochran Q test: 0.80), respectively. Increasing pre- and post-MT mean SBP levels were associated with lower odds of 3-month functional independence (ORadj, 0.86 [95% CI, 0.77–0.96]; I2=18%, P value for Cochran Q test: 0.30) and (ORadj, 0.80 [95% CI, 0.72–0.89]; I2=0%, P value for Cochran Q test: 0.51), respectively. In conclusion, elevated BP levels before and after MT are associated with adverse outcomes among patients with acute ischemic stroke with large vessel occlusion.

Chronic kidney disease (CKD) is associated with incident cardiovascular morbidity and mortality. Whether subclinical cardiovascular disease and target organ damage is associated with incident CKD is unknown. We investigated the relations of echocardiographic left ventricular mass (LVM) with incident CKD. We evaluated 2258 Framingham Offspring cohort participants (mean age, 57 years; 56% women) who underwent echocardiography at a routine examination and had an estimated glomerular filtration rate ≥60 mL/min per 1.73 m2. We used Cox proportional hazards regression with discrete time intervals to relate sex-standardized LVM (independent variable) to the incidence of CKD, defined as estimated glomerular filtration rate <60 L/min per 1.73 m2, on follow-up. During a median follow-up of 14.6 years, 373 (16.5%) participants developed incident CKD. Higher LVM was associated with higher risk of CKD after adjusting for prevalent cardiovascular disease, body mass index, systolic blood pressure, total and HDL (high-density lipoprotein) cholesterol, antihypertensive medication, smoking, and diabetes mellitus (hazard ratio, 1.15 [95% CI, 1.03–1.29]; P=0.017) per 1-SD increase in LVM g/m2. Further adjustment for baseline estimated glomerular filtration rate (adjusted hazard ratio, 1.16 [95% CI, 1.04–1.31]; P=0.010) and baseline urine albumin/creatinine ratio (adjusted hazard ratio, 1.18 [95% CI, 1.04–1.33]; P=0.009) slightly attenuated the association. In our community-based sample, LVM was associated with incident CKD prospectively, which suggests that the relations between CKD and subclinical cardiovascular disease may be bidirectional. Further studies are needed to confirm our findings.

Use of salt substitutes containing potassium chloride is a potential strategy to reduce sodium intake, increase potassium intake, and thereby lower blood pressure and prevent the adverse consequences of high blood pressure. In this review, we describe the rationale for using potassium-enriched salt substitutes, summarize current evidence on the benefits and risks of potassium-enriched salt substitutes and discuss the implications of using potassium-enriched salt substitutes as a strategy to lower blood pressure. A benefit of salt substitutes that contain potassium chloride is the expected reduction in dietary sodium intake at the population level because of reformulation of manufactured foods or replacement of sodium chloride added to food during home cooking or at the dining table. There is empirical evidence that replacement of sodium chloride with potassium-enriched salt substitutes lowers systolic and diastolic blood pressure (average net Δ [95% CI] in mm Hg: –5.58 [–7.08 to –4.09] and –2.88 [–3.93 to –1.83], respectively). The risks of potassium-enriched salt substitutes include a possible increased risk of hyperkalemia and its principal adverse consequences: arrhythmias and sudden cardiac death, especially in people with conditions that impair potassium excretion such as chronic kidney disease. There is insufficient evidence regarding the effects of potassium-enriched salt substitutes on the occurrence of hyperkalemia. There is a need for additional empirical research on the effect of increasing dietary potassium and potassium-enriched salt substitutes on serum potassium levels and the risk of hyperkalemia, as well as for robust estimation of the population-wide impact of replacing sodium chloride with potassium-enriched salt substitutes.

Hypertension, a multifactorial disorder resulting from the interplay between genetic predisposition and environmental risk factors, affects ≈30% of adults. Emerging evidence has shown that nonalcoholic fatty liver disease (NAFLD), as an underestimated metabolic abnormality, is strongly associated with an increased risk of incident prehypertension and hypertension. However, the role of NAFLD in the development of hypertension is still obscure and is highly overlooked by the general public. Herein, we highlight the epidemiological evidence and putative mechanisms focusing on the emerging roles of NAFLD in hypertension, with the purpose of reinforcing the notion that NAFLD may serve as an independent risk factor and an important driving force in the development and progression of hypertension. Finally, we also briefly summarize the current potential treatments for NAFLD that might also be beneficial approaches against hypertension.

Fragmented investigation has masked the overall picture for causes of cardiovascular disease (CVD). Among the risk factors for CVD, high blood pressure (BP) is associated with the strongest evidence for causation and it has a high prevalence of exposure. Biologically, normal levels of BP are considerably lower than what has typically been characterized as normal in research and clinical practice. We propose that CVD is primarily caused by a right-sided shift in the population distribution of BP. Our view that BP is the predominant risk factor for CVD is based on conceptual postulates that have been tested in observational investigations and clinical trials. Large cohort studies have demonstrated that high BP is an important risk factor for heart failure, atrial fibrillation, chronic kidney disease, heart valve diseases, aortic syndromes, and dementia, in addition to coronary heart disease and stroke. In multivariate modeling, the presumed attributable risk of high BP for stroke and coronary heart disease has increased steadily with progressive use of lower values for normal BP. Meta-analysis of BP-lowering randomized controlled trials has demonstrated a benefit which is almost identical to that predicted from BP risk relationships in cohort studies. Prevention of age-related increases in BP would, in large part, reduce the vascular consequences usually attributed to aging, and together with intensive treatment of established hypertension would eliminate a large proportion of the population burden of BP-related CVD.

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Previous studies have reported associations between ambient fine particle concentrations and preeclampsia; however, the impact of particulate pollution on early- and late-onset preeclampsia is understudied. Furthermore, few studies have examined the association between source-specific particles such as markers of traffic pollution or wood combustion on adverse pregnancy outcomes. Electronic medical records and birth certificate data were linked with land-use regression models in Monroe County, New York for 2009 to 2013 to predict monthly pollutant concentrations for each pregnancy until the date of clinical diagnosis during winter (November–April) for 16 116 births. Up to 30% of ambient wintertime fine particle concentrations in Monroe County, New York is from wood combustion. Multivariable logistic regression was used to separately estimate the odds of preeclampsia (all, early-, and late-onset) associated with each interquartile range increase in fine particles, traffic pollution, and woodsmoke concentrations during each gestational month, adjusting for maternal characteristics, birth hospital, temperature, and relative humidity. Each 3.64 µg/m3 increase in fine particle concentration was associated with an increased odds of early-onset preeclampsia during the first (odds ratio, 1.35 [95% CI, 1.08–1.68]), second (odds ratio, 1.51 [95% CI, 1.23–1.86]), and third (odds ratio, 1.25 [95% CI, 1.06–1.46]) gestational months. Increases in traffic pollution and woodsmoke during the first gestational month were also associated with increased odds of early-onset preeclampsia. Increased odds of late-onset preeclampsia were not observed. Our findings suggest that exposure to wintertime particulate pollution may have the greatest effect on maternal cardiovascular health during early pregnancy.

The objective of the current study is to use comparative and functional genomic analysis to help to understand the biological mechanism mediating the effect of single nucleotide polymorphisms (SNPs) on blood pressure. We mapped 26 585 SNPs that are in linkage disequilibrium with 1071 human blood pressure–associated sentinel SNPs to 9447 syntenic regions in the mouse genome. Approximately 21.8% of the 1071 linkage disequilibrium regions are located at least 10 kb from any protein-coding gene. Approximately 300 blood pressure–associated SNPs are expression quantitative trait loci for a few dozen known blood pressure physiology genes in tissues including specific kidney regions. Blood pressure–associated sentinel SNPs are significantly enriched for expression quantitative trait loci for blood pressure physiology genes compared with randomly selected SNPs (P<0.00023, Fisher exact test). Using a newly developed deep learning method and other methods, we identified SNPs that were predicted to influence the conservation of CTCF (CCCTC-binding factor) binding across cell types, transcription factor binding, mRNA splicing, or secondary structures of RNA including long noncoding RNA. The SNPs were more likely to be located in CTCF-binding regions than what would be expected from the whole genome (P=4.90×10−7, Pearson χ2 test). One example synonymous SNP rs9337951 was predicted to influence the secondary structure of its host mRNA JCAD (junctional cadherin 5 associated) and was experimentally validated to influence JCAD protein expression. These findings provide an extensive comparative and functional genomic resource for developing experiments to test the functional significance of human blood pressure–associated SNPs in human cells and animal models.

Increased blood pressure (BP) variability (BPV) is an independent risk factor of cardiovascular events among hypertensive patients. The arterial baroreceptor reflex is a powerful regulator of BP and attenuates BPV via a sympathetic negative feedback control. Conventional baroreceptor activation therapy (cBAT) electrically stimulates the carotid baroreceptors with constant stimulation parameters. While cBAT lowers BP, it does not mount a pressure feedback mechanism. We hypothesized that baroreceptor activation therapy with a pressure feedback system (smart BAT [sBAT]) is able to reduce BPV as well as lower BP. We developed sBAT that electrically stimulated baroreceptors at a frequency proportional to the difference between instantaneous BP and a preset reference pressure, and compared its performance with cBAT. In 14-week-old spontaneously hypertensive rats (n=6), we implanted BP telemeter and created impaired arterial baroreceptors by modified sino-aortic denervation. One week after surgical preparation, we administered sBAT, cBAT or no stimulation (sham) for 15 minutes and compared BP and BPV under freely moving condition. Both cBAT and sBAT significantly lowered mean BP (sham, 141.3±12.8; cBAT, 114.3±11.4; and sBAT, 112.0±7.3 mm Hg). Conventional BAT did not affect BPV at all, while sBAT significantly reduced BPV (sham, 15.4±2.6; cBAT, 16.0±5.2; and sBAT, 9.7±3.3 mm Hg). sBAT also prevented transient excessive BP rise and fall. In conclusion, sBAT was capable of reducing BP and attenuating BPV in hypertensive rats with impaired baroreceptor. sBAT is a novel treatment option for hypertensive patients with increased BPV.

Increasing evidence suggests a role for the ET (endothelin) system in preeclampsia. Hence, blocking this system with endothelin receptor antagonists (ERAs) could be a therapeutic strategy. Yet, clinical studies are lacking due to possible teratogenic effects of ERAs. In this study, we investigated the placental transfer of ERAs and their effect on ET-1-mediated vasoconstriction. Term placentas were dually perfused with the selective ETAR (ET type A receptor) antagonists sitaxentan and ambrisentan or the nonselective ETAR/ETBR antagonist macitentan and subsequently exposed to ET-1 in the fetal circulation. ET-1 concentration-response curves after incubation with sitaxentan, ambrisentan, macitentan, or the selective ETBR antagonist BQ-788 were also constructed in isolated chorionic plate arteries using wire-myography, and gene expression of the ET-system was quantified in healthy and early onset preeclamptic placentas. At steady state, the mean fetal-to-maternal transfer ratios were 0.32±0.05 for sitaxentan, 0.21±0.02 for ambrisentan, and 0.05±0.01 for macitentan. Except for BQ-788, all ERAs lowered the response to ET-1, both in the perfused cotyledon and isolated chorionic plate arteries. Placental gene expression of ECE-1, ETAR, and ETBR were comparable in healthy and preeclamptic placentas, while ET-1 expression was higher in preeclampsia. Our study is the first to show direct transfer of ERAs across the term human placenta. Furthermore, ETAR exclusively mediates ET-1-induced constriction in the fetoplacental vasculature. Given its limited transfer, macitentan could be considered as potential preeclampsia therapy. Extending knowledge on placental transfer to placentas of preeclamptic pregnancies is required to determine whether ERAs might be applied safely in preeclampsia.

Although the importance of office prehypertension/high normal blood pressure (BP) has been well documented, the significance of ambulatory prehypertension (AmbPreHT) has not been determined. We analyzed markers of target organ damage and hemodynamics in adolescents with AmbPreHT in comparison with hypertensive and normotensive subjects. Out of 304 white patients aged 15.0±2.5 years with office hypertension, 30 children had AmbPreHT and were compared with 66 normotensive healthy children and 92 children with true hypertension (elevated office, ambulatory, and central BP), 22 had ambulatory hypertension (AmbHT), and 70 had severe AmbHT (SevAmbHT). Stroke volume and cardiac output were greater in AmbPreHT compared with patients with normotension but did not differ between AmbPreHT, AmbHT, and SevAmbHT. Similarly, AmbPreHT, AmbHT, and SevAmbHT had similar total peripheral resistance, lower than patients with normotension (P<0.05). Central systolic BP was higher in patients with AmbPreHT, AmbHT, and SevAmbHT compared with normotensives (P<0.01). In all 3 groups, the carotid intima-media thickness Z scores were significantly higher than in normotensive (P<0.001). AmbPreHT and AmbHT patients had higher left ventricular mass index and prevalence of left ventricular hypertrophy compared with normotensive but lower compared with SevAmbHT (P<0.001). Pulse wave velocity Z scores were increased in patients with AmbPreHT, AmbHT, and SevAmbHT compared with patients with normotension (P<0.01). Multiple regression analysis showed that body mass index Z score, central systolic BP, and uric acid levels were significant independent predictors of left ventricular mass index. In conclusion, patients with AmbPreHT presented similar cardiovascular adaptations to those observed in patients with hypertensive and may be at risk of developing cardiovascular events.

Left ventricular hypertrophy is a strong predictor of prognosis in hypertension. Physical activity is associated with higher left ventricular mass but also reduced risk of cardiovascular outcomes.The aims were to explore whether (1) presence of hypertension modifies the association between physical activity and left ventricular mass; (2) the beneficial association between physical activity and prognostic outcome is modified by left ventricular hypertrophy. Randomly selected number of 3078 persons from the general population underwent echocardiogram. Left ventricular mass was indexed to body surface area. Level of physical activity was self-reported: inactivity, light activity, and moderate/high activity. Blood pressure was measured in rest: normal BP (<140/90 mm Hg) and hypertension (≥140/90 mm Hg or in pharmacological treatment for hypertension). Presence of hypertension modified the association between physical activity and left ventricular mass index significantly (test for interaction: P=0.01): in normal BP, higher levels of physical activity were associated with significantly higher left ventricular mass index (P<0.001), but this was not present in hypertension (P=0.90). Level of physical activity was associated with reduction in mortality and cardiovascular outcome independent of the presence of LVH (Persons with LVH: light activity HR, 0.77 [0.52–1.15], moderate/high activity HR, 0.61 [0.38–0.97]; test for interaction between LVH and level of physical activity P=0.71). In conclusion, persons with normal BP had higher left ventricular mass index at increased levels of physical activity, whereas this association was not present among persons with hypertension. Level of physical activity was associated with better prognosis independent of whether left ventricular hypertrophy was present or not.

In healthy pregnancy, glucose and oxygen availability are essential for fetal growth and well being. However, how substrate delivery and fetal uptake are affected in human pregnancy complicated by fetal growth restriction (FGR) is still unknown. Here, we show that the human FGR fetus has a strikingly reduced umbilical uptake of both oxygen and glucose. In 30 healthy term and 32 FGR human pregnancies, umbilical volume flow (Qumb) and parallel umbilical vein (uv) and artery (ua) blood samples were obtained at elective Cesarean section to calculate fetal glucose and oxygen uptake as Qumb · Δ (uv−ua) differences. Umbilical blood flow was significantly lower in FGR pregnancy (−63%; P<0.001) but not when normalized for fetal body weight. FGR pregnancy had significantly lower umbilical oxygen delivery and uptake, both as absolute values (delivery: −78%; uptake: −78%) and normalized (delivery: −50%; uptake: −48%) for fetal body weight (all P<0.001). Umbilical glucose absolute delivery and uptake were significantly reduced (delivery: −68%; uptake: −72%) but only glucose uptake was decreased when normalized for fetal body weight (−30%; P<0.05). The glucose/oxygen quotient was significantly increased (+100%; P<0.05) while glucose clearance was significantly decreased (71%; P<0.001) in FGR pregnancy (both P<0.05). The human fetus in FGR pregnancy triggers compensatory mechanisms to reduce its metabolic rate, matching the proportion of substrate consumption relative to oxygen delivery as a survival strategy during complicated pregnancy.

Hypertensive disorders during pregnancy are an important risk to mother and fetus, frequently necessitating antihypertensive treatment. Data describing the safety of in utero exposure to antihypertensive treatment is conflicting, with many studies suffering from significant methodological issues, such as inappropriate study design, small sample sizes, and no untreated control group. We conducted a retrospective cohort study using linked routinely collected healthcare records for 268 711 children born 2010–2014 in Scotland to assess outcomes following in utero exposure to antihypertensive medication. We identified a cohort of 265 488 eligible children born over the study period; of which, 2350 were exposed to in utero antihypertensive medication, 4391 exposed to treated late-onset hypertension, and 7971 exposed to untreated hypertension during pregnancy. Untreated hypertension was associated with increased risk of preterm birth (adjusted risk ratio [aRR], 1.15 [99% CI, 1.01–1.30]), low birth weight (aRR, 2.01 [99% CI, 1.72–2.36]) and being small for gestational age (aRR, 1.50 [99% CI, 1.35–1.66]), while in utero antihypertensive exposure was also associated with preterm birth (aRR, 3.12 [99% CI, 2.68–3.64]), low birth weight (aRR, 2.23 [99% CI, 1.79–2.78]), and being small for gestational age (aRR, 2.13 [99% CI, 1.81–2.52]). Late-onset hypertension was also associated with preterm birth (aRR, 2.21 [99% CI, 1.86–2.62]), low birth weight (aRR, 2.06 [99% CI, 1.74–2.43]), and being small for gestational age (aRR, 1.90 [99% CI, 1.68–2.16]). Our results suggest that hypertension is a key risk factor for low birth weight and preterm birth. Although preterm birth may be associated with antihypertensive medication exposure during pregnancy, these associations may reflect increasing hypertension severity necessitating treatment.

In addition to the circulating renin-angiotensin system, activation of the brain renin-angiotensin system plays an important role in the pathophysiology of hypertension. One of the major components of the brain renin-angiotensin system implicated in the development of hypertension is Ang III (angiotensin III). Brain Ang III, produced from Ang II (angiotensin II) by APA (aminopeptidase A), exerts a tonic stimulatory control over blood pressure in hypertensive rats. Targeting Ang III by inhibiting brain APA is now considered a potentially important target in the management of hypertension. This has led to development of RB150, an orally active prodrug of the specific and selective APA inhibitor, EC33. Orally administered RB150 crosses the gastrointestinal and blood-brain barriers, enters the brain where it generates 2 active molecules of EC33 that block brain APA activity. This results in decreased brain Ang III formation and reduced blood pressure in hypertensive rats. The RB150-induced blood pressure decrease is due to a reduced vasopressin release, which increases diuresis, reducing extracellular volume, a decrease in sympathetic tone, leading to a reduction of vascular resistances, and the improvement of the baroreflex function. RB150 was renamed firibastat by the World Health Organization. Phase Ia/Ib clinical trials showed that firibastat is clinically and biologically well tolerated in healthy volunteers. Clinical efficacy of firibastat in hypertensive patients was, therefore, demonstrated in 2 phase II studies. Accordingly, firibastat could represent the first drug of a novel class of antihypertensive drugs targeting the brain renin-angiotensin system.

Hypertension among young people is common, affecting 1 in 8 adults aged between 20 and 40 years. This number is likely to increase with lifestyle behaviors and lowering of hypertension diagnostic thresholds. Early-life factors influence blood pressure (BP) although the mechanisms are unclear; BP tracks strongly within individuals from adolescence through to later life. Higher BP at a young age is associated with abnormalities on heart and brain imaging and increases the likelihood of cardiovascular events by middle age. However, diagnosis rates are lower, and treatment is often delayed in young people. This reflects the lack of high-quality evidence that lowering BP in young adults improves cardiovascular outcomes later in life. In this review, we evaluate the current evidence regarding the association between BP in young adult life and adverse cardiovascular outcomes later in life. Following this, we discuss which young people with raised BP should be investigated for secondary causes of hypertension. Third, we assess the current models to assess cardiovascular risk and show a lack of validation in the younger age group. Fourth, we evaluate the evidence for lifestyle interventions in this age group and demonstrate a lack of persistence in BP lowering once the initial intervention has been delivered. Fifth, we address the pros and cons of drug treatment for raised BP in young people. Finally, there are unique life events in young people, such as pregnancy, that require specific advice on management and treatment of BP.

Current cardiovascular pharmacotherapy targets maladaptive overactivation of the renin-angiotensin-aldosterone system (RAAS), which occurs throughout the continuum of cardiovascular disease spanning from hypertension to heart failure with reduced ejection fraction. Over the past 16 years, 4 prospective, randomized, placebo-controlled clinical trials using candesartan, perindopril, irbesartan, and spironolactone in patients with heart failure with preserved ejection fraction (HFpEF) failed to demonstrate increased efficacy of RAAS blockade added to guideline-directed medical therapy. We reappraise these trials and their weaknesses, which precluded statistically significant findings. Recently, dual-acting RAAS blockade with sacubitril-valsartan relative to stand-alone valsartan failed to improve outcome in the PARAGON-HF trial (Efficacy and Safety of LCZ696 Compared with Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction). The majority of patients with HFpEF experience hypertension, frequently with subclinical left ventricular dysfunction, contributed to by comorbidities such as coronary disease, diabetes mellitus, overweight, and atrial fibrillation. Contrasting the findings in HFpEF, trials evaluating RAAS blockade on either side of HFpEF on the cardiovascular continuum in patients with high-risk hypertension and heart failure with reduced ejection fraction, respectively, showed positive outcomes. We do not have a biologically plausible explanation for such divergent efficacy of RAAS blockade. Based on considerations of well-established clinical efficacy in hypertension and heart failure with reduced ejection fraction and the shortcomings of aforementioned clinical trials in HFpEF, we argue that RAAS blockers including MRAs (mineralocorticoid receptor antagonists; aldosterone antagonists) should be used in the treatment of patients with HFpEF.

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