Ernesto L. Schiffrin

The mechanisms that cause hypertension remain elusive despite more than a century of investigation. Some of its triggers include aging, sex, salt, diet, stress, experience with adversity, socio-cultural-economic disparities, and poor-quality sleep. The renin-angiotensin-aldosterone and the endothelin systems and other hormones contribute to varying degrees to the rise in BP and target organ damage. It has become increasingly recognized that inflammation and the innate and adaptive immune systems play a role in the etiopathogenesis of hypertension. We review here the participation of different cellular and molecular (genetic and epigenetic) mechanisms that play a role in hypertension via the immune system, including neutrophil extracellular traps, memory T cells, and aldosterone-modulated trained immunity mediated by monocytes/macrophages. Molecular mechanisms, including the effects of neutrophil gelatinase-associated lipocalin as an immunomodulator, and the role of isolevoglandins in mediating oxidative stress-induced activation of the adaptive immune system are analysed. We conclude by summarizing potential therapeutic avenues to address inflammation in hypertension.

Objectives: Mice with tamoxifen-inducible endothelium-restricted human endothelin-1 (ET-1) overexpression (ieET-1) exhibited blood pressure elevation after 3 weeks and 3 months, and vascular injury after 3 months. We hypothesised that ET-1 overexpression-induced vascular injury is mediated by gene expression dysregulation. Methods: Male ieET-1 mice and mice expressing a tamoxifen-inducible Cre recombinase in endothelial cells were induced with tamoxifen and studied 3-week and 3-month post-treatment. MicroRNA and gene expression were profiled in mesenteric arteries by RNA-sequencing and validated by RT-qPCR. Aorta was used for immunofluorescence microscopy. Results: KH domain containing RNA binding signal transduction associated 3 ( Khdrbs3 ) was the top upregulated gene identified by RNA-sequencing ( P = 8x10 ⁻¹² ) validated by RT-qPCR ( P < 0.001) after 3-week and 3-month ET-1 overexpression. KHDRBS3 protein was increased in aortic endothelial and vascular smooth muscle cells (VSMCs) after 3-month ET-1 overexpression. KHDRBS3 is a splicing regulator of various mRNAs, including human vascular endothelial growth factor A ( VEGFA ) 165 isoform with exon 7 retention. Three-month ET-1 overexpression upregulated isoforms Vegfa ₁₆₄ containing exon 7 and Vegfa ₁₈₈ retaining exons 6 and 7, and downregulated Vegfa ₁₂₀ isoform lacking both exons ( P < 0.05). Analysis of RNA-immunoprecipitation-sequencing of myocardium of patients with dilated cardiomyopathy identified VEGFA and four key VSMC-specific pre-mRNAs as KHDRBS3 targets. Reanalysis of RNA-sequencing data of angiotensin II-infused mice revealed a high correlation between ET-1 ( Edn1 ) and Khdrbs3 mRNAs in mesenteric arteries ( r ² = 0.82, P = 3.7 x 10 ⁻⁹ ). Conclusion: Endothelial human ET-1 overexpression induced RNA splicing via enhanced Khdrbs3 expression, which may play a role in vascular injury, and could represent a therapeutic target in hypertension.

Over one-third of Canadians with hypertension do not achieve recommended blood pressure (BP) targets despite availability of effective treatments. Renal sympathetic nerve denervation (RDN) is a recently approved, minimally invasive treatment for hypertension being offered in multiple Canadian centers. How best to implement this procedure in contemporary Canadian clinical practice remains unclear. Herein, we provide a Canadian hypertension specialist viewpoint on use of RDN in Canada. We review the rationale for, and evidence supporting, the use of RDN and discuss, using 2 clinical cases, its potential therapeutic role. We note that RDN has effectively lowered BP in multiple, sham-controlled, randomized clinical trials and has a favorable safety profile. Economic models indicate that it is cost-effective in the Canadian context. Conversely, the BP-lowering effect is relatively modest; no well-established method to pre-identify responders exists; cardiovascular endpoint data supporting use of RDN are lacking; and no clear funding model is currently in place in Canada. Accordingly, we suggest that use of RDN be reserved for willing patients with severely elevated BP despite the use of first-line conventional therapies who have had secondary causes excluded. Examples include patients with resistant hypertension or moderate or severe hypertension and multiple drug intolerance syndrome. In view of its recent approval and known operator-dependency, RDN should be offered solely through programmatic, multidisciplinary collaboration between hypertension specialists and experienced interventionalists using a shared decision-making approach with the patient. Funding deployment should target such programs and sites should carefully monitor their outcomes to confirm comparability to the published literature.

Aldosterone, produced by adrenal glomerulosa cells, stimulated by angiotensin II, adrenocorticotrophin, and potassium, and inhibited by natriuretic peptides, plays a role in hypertension and CKD development and progression. Its effects are mediated by nuclear mineralocorticoid receptors inducing genomic effects and putatively by a membrane G-protein–coupled receptor which could be the G-protein–coupled estrogen receptor, triggering nongenomic actions. The classical effect of aldosterone is on the distal nephron to retain Na ⁺ and water and excrete potassium, contributing to electrolyte and extracellular volume control. However, aldosterone also acts by stimulating oxidative stress through different signaling pathways that include tyrosine kinases and mitogen-activated protein kinases to induce inflammation and fibrosis in blood vessels, the kidney, and the heart. The actions of aldosterone also lead to endothelial dysfunction, which participates in its effects on target organs, including progression of hypertension. Blockade of mineralocorticoid receptor or inhibition of aldosterone generation lowers BP and protects target organs, reducing progression of CKD. All these actions are reviewed, with an emphasis on the effects on the kidney.

There have been few new treatments introduced for hypertension in the last thirty years. The endothelin (ET) system was discovered in 1988, and in the following years, it was demonstrated that it participated in the elevation of blood pressure and vascular remodeling in experimental models of hypertension, particularly those with more severe forms of hypertension. Several selective and dual antagonists of ETA receptors (ETARs) and ETB receptors (ETBRs) were developed, but none reached marketing for human hypertension. Following a successful trial in resistant hypertension, a novel antihypertensive agent has been approved in Europe and in the U.S.A.: the dual ETAR/ETBR antagonist aprocitentan, which was recently approved for the treatment of hypertension in combination with other antihypertensive drugs, to lower blood pressure in adult patients who are not adequately controlled on other drugs. Thus, the time has finally arrived for ET antagonists in hypertension.

Hypertension is associated with vascular injury characterized by vascular dysfunction, remodeling, and stiffening, which contributes to end-organ damage leading to cardiovascular events and potentially death. Innate (macrophages and dendritic cells), innate-like (γδ T cells) and adaptive immune cells (T and B cells) play a role in hypertension and vascular injury. Perivascular adipose tissue that is the fourth layer of the blood vessel wall is an important homeostatic regulator of vascular tone. Increased infiltration of immune cells in perivascular adipose tissue in hypertension results in generation of oxidative stress and production of cytokines that may cause vascular injury. This review presents an overview of the role of the different immune cells that infiltrate the perivascular adipose tissue and are involved in the pathophysiology of hypertension.

Discrimination in cardiovascular healthcare, particularly concerning hypertension treatment, is a significant and complex issue in Latin America, driven by biases related to gender, ethnicity, and economic status. Although cardiovascular disease is the leading cause of death worldwide, disparities in healthcare delivery endure, especially impacting marginalized populations. Women, ethnic minorities, and economically disadvantaged groups encounter considerable barriers, including underrepresentation in clinical research, delayed diagnoses, and unequal access to guideline-recommended treatments. Economic disparities maintain a divided healthcare system in which the quality of treatment often directly correlates with socioeconomic status, reinforcing inequities and adversely affecting health outcomes in lower-income communities. Ethnic discrimination, stemming from deeply ingrained social biases, leads to inadequate care and limited access to advanced medical technologies, disproportionately impacting indigenous and Afro-descendant populations. Addressing these systemic inequities requires comprehensive strategies that ensure equitable participation in clinical trials, develop tailored public health policies sensitive to socioeconomic and cultural contexts, and implement targeted educational initiatives. Healthcare systems must actively dismantle entrenched biases, improve access for economically disadvantaged communities, and guarantee that ethnic minorities receive treatment of equal quality. The Inter-American Society of Hypertension emphasizes that removing these discriminatory barriers reduces the burden of cardiovascular disease and enhances overall health outcomes across Latin America. This document endorses consensus recommendations detailed in positions 1 through 4, which tackle specific challenges related to personalized care, racial biases in treatment algorithms, socioeconomic healthcare inequalities, and gender disparities in hypertension management.