From the Editor-in-Chief: Issue at a glance

The current issue of the American Journal of Hypertension for October 2021 begins with a review by J. Youwakim and H. Girouard1 on mechanistic links between hypertension and neurodegenerative diseases. Low-grade chronic inflammation systemically and in the central nervous system contributes to the physiopathology of hypertension. Inflammation could represent a mediator between hypertension and neurodegenerative diseases by decreases in cerebral blood flow or disruption of the blood brain barrier. The latter could allow inflammatory cells and neurotoxic molecules to enter the brain parenchyma, which may impact brain function including cognition, contributing to neurodegenerative diseases. In this review the authors address relationships between hypertension, systemic inflammation, cerebrovascular function, neuroinflammation and brain dysfunction, and the potential of immunotherapy to treat hypertension and associated cerebrovascular risk. Two commentaries follow, one by Sebastião et al.2 on factors associated with maintaining normal blood pressure (BP) from a young age into midlife, and one by Basdeki et al.3 on lifestyle interventions and ability to avoid the need for guideline-directed antihypertensive drugs, that will be both discussed together with the original studies they refer to. The first original paper is a brief communication that reports findings from the CARDIA study by Reges et al.4 that evaluated which were the most critical risk factors associated with maintaining normal BP over 30 years, and which were the sectors of the population most able to do so. Included in this study were subjects aged 18 to 30 years with normal BP level at the baseline visit (Y0, 1985-6). Of 3,156 participants, 35.9% maintained normal BP during the follow-up period. Systolic BP within the normal range, race, and BMI were the most important factors for maintaining normal BP throughout midlife. Participants with the highest probability to maintain normal BP were those with a baseline systolic BP ≤92 mmHg and White women with baseline BMI<23 kg/m2. Among Black participants aged >26.5 years with BMI>27 kg/m2, only 5.4% maintained normal BP throughout midlife. The study supports the importance of early life factors for later life systolic BP. It underlines the importance of efforts to maintain ideal levels of risk factors for hypertension at a young age. It is accompanied by a Commentary by Sebastião et al.2 that discusses whether classification trees help in predicting the consequences of risk factors for hypertension. The commentary argues that education, the only measure of socioeconomic status included in the study by Reges et al.,4 does not fully account for the influence of income, socioeconomic mobility, and neighborhood characteristics, all of which contribute to the risk of hypertension, particularly among African Americans. Many have indeed maintained that race “may be a marker for psychosocial factors resulting from societal disparities/racism…”, which as paraphrased from Sebastião et al.,2 requires a more profound analysis of race as a risk factor, biological race being in fact rarely the variable of concern, the true risk factor most often being racial inequality, structural racism, and socioeconomic factors associated with being Black in the US. The next brief communication by Lambert et al.5 evaluated the potential role of religious leaders to improve hypertension control in their communities in rural sub-Saharan Africa where hypertension is a growing public health emergency. They carried out 31 in-depth interviews with Christian and Muslim religious leaders in rural Tanzania focused on the understanding about hypertension of these religious leaders and their potential participation in advocating for reduction of blood pressure. These authors found that perceptions about causes, treatment, and complications of hypertension were influenced by religious beliefs. Religious beliefs could facilitate participation in hypertension care through religious texts supporting use of biomedical care. These religious leaders were also favorable to promotion of hypertension control in their communities, and this was consistent between religions and genders. The authors concluded that religious leaders could be appealed to, in order to improve hypertension control in rural sub-Saharan Africa, and perhaps elsewhere. Following these brief communications is a paper by Matsuoka et al.6 that in a retrospective observational cross-sectional analysis using the JMDC Claims Database, analyzed 280,599 subjects not taking any antihypertensive medications and examined the association between the BP classification defined by the 2017 American College of Cardiology/American Heart Association guideline and the prevalence of retinal atherosclerosis with retinal photographs. Using the Keith–Wagener–Barker classification, they found grade ≥1 in 3.2% in subjects with normal BP, 5.2% in elevated BP, 7.7% in stage 1 hypertension, and 18.7% in stage 2 hypertension. Among 92,121 subjects without other CVD risk factors, elevated BP, stage 1 hypertension and stage 2 hypertension were associated with a higher prevalence of retinal atherosclerosis. These results suggest that retinal atherosclerosis may be found already in persons with elevated BP and stage 1 hypertension. In the next manuscript, Speer et al.7 studied anthropometric and physical measurements, as well as blood and saliva biomarkers, as predictors for hypertension using datasets from the 2008 Health and Retirement Study in 2,924 participants with a mean age of 75 years using binary logistic regression. Males had 2.3 times the odds of being hypertensive if they were obese, whereas females had 1.7 times the odds if overweight, and 2.4 times if obese. In females for every 1-year increase in age there was a 5.1% increase in odds of developing hypertension. CRP >3 mg/L enhanced odds of developing hypertension 1.4 times. Thus, BMI is a predictor for hypertension, and age and CRP are predictors for females. Sex differences and life stage need to be taken into account when evaluating risk of developing hypertension in order to promote healthy aging. The following article examines the microbiome, but here in blood in contrast to the usual investigation of the gut microbiome. Jing et al.8 studied 150 patients with newly diagnosed hypertension compared to matched normotensive subjects in a nested case-control study in which they characterized the blood microbiome using bacterial 16S ribosomal RNA gene sequencing. The diversity of the blood microbiome in controls was significantly higher than in the hypertensive group. Compared with controls, the relative abundance of the Proteobacteria phylum was significantly increased whereas relative abundance of the Firmicutes and Bacteroidetes phyla were significantly reduced in the hypertensive individuals. The risk of hypertension was directly associated with the relative abundance of Acinetobacter, Sphingomonas, and Staphylococcus. In addition, the relative abundance of Pseudomonas was positively correlated to total cholesterol levels, and the relative Staphylococcus level was positively correlated to HDL-cholesterol levels. The authors concluded that composition of the blood microbiome is significantly associated with the development of hypertension. High salt stimulates the expression of miR-429 in the renal medulla, which induces mRNA downregulation of HIF prolyl-hydroxylase 2 (PHD2), an enzyme that promotes degradation of hypoxia-inducible factor (HIF)-1α, and increases the HIF-1α-mediated activation of antihypertensive genes in the renal medulla, leading to increased sodium excretion. However, high salt-induced increase of miR-429 is not observed in Dahl S rats. In the study in the present issue, Zhu et al.9 used lentiviruses encoding rat miR-429 to transfect the latter into the renal medulla in uninephrectomized Dahl S rats to establish if miR-429 would reduce PHD2 levels, increase antihypertensive gene expression in the renal medulla and attenuate salt-sensitive hypertension in Dahl S rats. Expression of miR-429 in the renal medulla indeed decreased PHD2 levels, and upregulated the HIF-1α target gene NOS2, which enhanced antihypertensive effects after high-salt intake in Dahl S rats. Overexpression of miR-429 transgene in the renal medulla significantly improved the pressure natriuresis response and urinary sodium excretion, and accordingly attenuated salt-sensitive hypertension in Dahl S rats. These results suggest that impaired miR-429-mediated PHD2 inhibition in response to high salt in the renal medulla may be a novel mechanism for salt-sensitive hypertension in Dahl S rats. Stimulation of the miR-429 pathway could be a therapeutic approach for salt-sensitive hypertension. Fadel et al.10 studied the usefulness of a visual analytics dashboard in addition to electronic health records (HER) in managing hypertension in primary care within an urban, academic internal medicine clinic using simulated patient encounters: one with a standard EHR, and the second using EHR associated with a visual dashboard that included graphical blood pressure trends with guideline-directed targets, calculated ASCVD risk score, and medications. Use of the dashboard with the EHR compared to use of the EHR alone was associated with greater adherence to prescribing guidelines and correct identification of BP targets. Encounter time was shortened when using the combined dashboard/EHR. The authors concluded that the advantages of this approach justified wider testing in clinical practice. That single-pill combinations (SPC) are superior to monotherapy in controlling BP as initial treatment has already been suggested. Rea et al.11 in this issue compared adherence to antihypertensive therapy between newly treated patients in who monotherapy or a 2-drug SPC was initially prescribed among 63,448 residents of the Lombardy Region of Italy during 2016, and who were followed for 1 year after the first prescription. Approximately 46% and 17% of patients showed high and poor adherence, respectively. The 15% of patients initially treated with a SPC were more likely to be highly adherent to antihypertensive treatment in comparison to patients initially under monotherapy (85%), independent of sex, age, clinical status, and any kind of SPC. Thus, in a real-life setting, patients who were initially prescribed a 2-drug SPC were more frequently adherent to antihypertensive treatment than those initially treated with a single drug. In the next article, Basson et al.12 investigated how CCBs affect progression of blood pressure variability (BPV) and whether long term adverse effects (AE) of BPV differ after CCB treatment compared to treatment with other antihypertensive agents in a retrospective analysis of 25,268 US veterans. These subjects had been followed for 3 years without antihypertensive therapy. They were started on a single class of antihypertensive agents (thiazides, CCBs, ACE inhibitors, or beta blockers [BBs]), treated for 6 years, and then followed for 3 additional years. High BPV and BB or thiazide use were associated with increased AE risk. The effects of other medications except for BBs on AE and mortality were independent of the patients’ BPV. The authors concluded that possible deleterious effects of thiazides should be considered in relation to the study population, who were mostly male and received only a single class of antihypertensive drugs. While CCBs could improve BPV over time, this study did not support choosing CCBs over other agents specifically to reduce risk associated with BPV. The following paper by Hinderliter et al.13 looked at the effects of lifestyle modification on calculated CVD risk and on indications for BP-lowering drugs in subjects with untreated hypertension among 144 adults with a mean age of 52 years and BP 130–160/80–99 mm Hg. Patients were randomized to 16 weeks of DASH (Dietary Approaches to Stop Hypertension) diet plus behavioral weight management (DASH + WM), DASH diet alone (DASH), or Usual Care. The 10-year CVD risk was 5.7%. The adjusted 10-year risk fell to 4.4% in the DASH + WM group and to 5.0% in the DASH arm, but was unchanged (5.7%) in the Usual Care controls. The percentage of participants with guideline-based indication for antihypertensive agent prescription fell from 51% to 18% in the DASH + WM group and from 48% to 22% in the DASH group; and was unchanged in the Usual Care group. Thus, men and women with mildly elevated BP can lower their calculated CVD risk with lifestyle interventions, which can as well decrease the number of individuals for who guideline-directed antihypertensive medication is indicated. The paper is accompanied by a Commentary by Basdeki et al.3 who raise a word of caution, since although similar research efforts should be encouraged, in many healthcare systems such multidisciplinary long term lifestyle interventions may not be realistic. Kabayama et al.14 evaluated whether nurse-led alcohol guidance during outpatient visits helped control home blood pressure (HBP) in the morning among male hypertensive patients. In a randomized trial, male hypertensive patients who had excessive habitual alcohol drinking were assigned to nurse-led alcohol guidance or to a control group. At 6 months, the mean HBP was controlled in 55.6% of the participants in the intervention group but only in 16.7% in the control group. Alcohol consumption had also decreased significantly in the intervention group. These results confirmed the effectiveness of the nurse-led alcohol guidance to control the HBP in male patients with hypertension in an outpatient setting. Ji et al.15 investigated the protective effects of the novel peptide AEDPPE and lipopolysaccharide (LPS)-induced injury in the vascular endothelium in preeclampsia. They demonstrated that AEDPPE reduced the upregulation of antiangiogenic factors such as sFlt-1, ET-1 and tPA, and attenuated the reduction in mitochondrial potential induced by TNFα in HUVECs. As well, AEDPPE treatment exerted a countervailing effect on decreased tube formation and numbers of THP-1 monocytes attached to HUVECs triggered by TNFα. Cytokine−cytokine receptor interactions enriched many genes, effect in which TNF signaling may participate. In addition, cotreatment with LPS and AEDPPE reduced blood pressure elevation and proteinuria and improved kidney and placenta function. The authors suggest that these findings demonstrate that AEDPPE may improve endothelial dysfunction and could be a potential treatment for preeclampsia.

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