The brain's vasculature-from pial arteries through penetrating arterioles and the capillary bed to venous drainage-is enveloped by a narrow, compositionally elaborate perivascular space that provides the primary signaling interface between neural tissue and blood vessels. Here, we advance the principle that the geometry and composition of this space are not constant but change systematically along the vascular tree, and that perivascular space composition at these locations imposes biophysical constraints that dictate the fidelity and gain of neurovascular signaling. We argue that its narrow micro-to-nanodomain geometry, basement membrane sieving effects, and the anionic environment created by heparan sulfate proteoglycans favor small aqueous mediators-potassium, nitric oxide (NO), and adenosine-for rapid, spatially targeted blood flow control, while constraining lipophilic mediators, such as prostaglandins and epoxyeicosatrienoic acids, toward predominantly autocrine action. Reassessing glymphatic fluid flux as a proposed source of vascular mechanical input, we find that the relevant shear forces fall several orders of magnitude below the threshold required to engage canonical smooth muscle mechanotransduction, arguing against a direct mechanical role for perivascular flow. We then synthesize how hypertension degrades each layer of this system: perivascular space expansion dilutes mediator concentrations, barrier breakdown admits plasma proteins capable of sequestering signaling molecules, and inflammation dysregulates the vascular ion channels that serve as signaling effectors. Framing the perivascular space as a biophysically constrained signaling compartment helps reconcile disparate observations of mediator selectivity and fluid mechanics, identifies how its progressive disruption may contribute to cerebrovascular dysfunction associated with chronic hypertension, and may help identify novel targets for preventing or reversing cognitive decline and neurodegeneration.
Loop diuretics are first-line therapy for hypervolemia. They block the sodium-potassium-2-chloride cotransporter type 1 on the renal afferent arteriole that mediates vasoconstriction and the sodium-potassium-2-chloride cotransporter type 2 on the macula densa cells that mediates the tubuloglomerular feedback response and raises intrarenal pressure that inhibits the myogenic response. These should reduce afferent arteriolar vasoconstriction and increase the glomerular filtration rate; however, more often, the glomerular filtration rate is reduced. This has been attributed to diuretic-induced extracellular volume depletion that activates a systemic neurohormonal response. Accordingly, a fall in glomerular filtration rate can lead to strategies to restore body fluid volumes while reducing the diuretic dosage. Here, we review the regulation of renal hemodynamics during loop diuretic therapy. We propose that a passive, obstructive component of reduced renal blood flow combines with activation of renal afferent nerves, macula densa-derived renin release with intrarenal Ang II (angiotensin II) formation, and generation of vasoconstrictor prostaglandins and thromboxane to provide intrarenal mechanisms of passive and active increases in renal vascular resistance that together can reduce the glomerular filtration rate. The hypothesis that a reduction in the glomerular filtration rate with loop diuretics can derive from intrarenal mechanisms of vasoconstriction rather than from volume depletion suggests novel approaches to manage diuretic resistance and worsening renal function in heart failure.
Increased blood pressure variability (BPV) is associated with increased risk for dementia, independent of hypertension. The increased risk for dementia associated with high BPV includes probable Alzheimer disease (AD) dementia, but high BPV is also associated with increased risk of stroke and cerebral small vessel disease, which are commonly comorbid with AD. This raises the question of whether high BPV is independently predictive of AD-specific pathophysiology and neurodegeneration, which could have significant clinical implications. Fewer studies have directly addressed this question by examining whether higher BPV predicts future AD biomarker abnormalities that are specific to AD pathophysiology within the amyloid/tau/neurodegeneration framework. This narrative review summarizes current studies on this topic and discusses future directions in the investigation of elevated BPV as a risk factor for AD, the most common cause of dementia in older adults.
Also known as ATP6AP2, the PRR ([pro]renin receptor) was originally cloned over 2 decades ago as a component of the renin-angiotensin system due to its property of nonproteolytic activation of prorenin. After heated debates, this concept has been confirmed and expanded with advances in sPRR (soluble PRR) research. sPRR is a 28-kDa protein that is derived from the extracellular domain of PRR and is primarily released by site-1 protease. Circulating sPRR is elevated in patients with multiple diseases, including diabetes, hypertension, preeclampsia, and kidney disease. A decade ago, sPRR was found to have an antidiuretic function that occurs through the modulation of vasopressin signaling in the collecting duct. This finding signified the beginning of a new chapter in understanding the biological function of sPRR in multiple organ systems, particularly the kidney, and blood pressure regulation. In the past few years, numerous groundbreaking discoveries in this field have shed new light on the complex biology of sPRR, including its heterogeneity due to proteolysis and the multifaceted interaction between sPRR and the intrarenal renin-angiotensin system. The goal of this review is to summarize new advances in this emerging field of sPRR research.
BACKGROUND: Left ventricular hypertrophy (LVH) is frequently identified in patients with primary aldosteronism; determinants of LVH regression after targeted treatment are debated. We assessed LVH prevalence before and after adrenalectomy or mineralocorticoid receptor antagonist (MRA) therapy, identified determinants of LVH regression, and evaluated the relationship between patients’ outcomes and cardiac remodeling. METHODS: We retrospectively analyzed an international cohort of patients with primary aldosteronism from 36 referral centers in Spain, Italy, and Germany. Echocardiographic recordings were included at baseline and after at least 1 year of targeted treatment. Regression models were applied to identify parameters associated with LVH regression and changes in left ventricular mass index. RESULTS: Among 1454 patients (mean age, 51 years; 58.7% male) with primary aldosteronism, baseline LVH prevalence was 49.4%. Aldosterone, blood pressure, male sex, number of antihypertensive medications, and diabetes were associated with LVH. Of 473 patients with a follow-up echocardiography, 33.6% underwent adrenalectomy, 61.7% received MRA, and 4.7% were taking MRA postsurgery. After a median follow-up of 51 months, LVH regression was observed in 54.2% of patients (61.9% after adrenalectomy versus 48.6% with MRA treatment; P =0.043), and left ventricular mass index significantly decreased after both surgery and medical therapy. Higher pretreatment blood pressure and aldosterone levels were associated with a lower likelihood of LVH regression, regardless of treatment modality. Complete biochemical success was associated with greater left ventricular mass index reduction at follow-up. CONCLUSIONS: LVH regressed in over half the patients after targeted treatment, with left ventricular mass index decreasing after both adrenalectomy and MRA therapy. Baseline aldosterone levels were associated with LVH regression, independently of blood pressure load.
BACKGROUND:Primary aldosteronism is frequently caused by mutations in the KCNJ5 (potassium inwardly rectifying channel subfamily J member 5) gene, encoding a G-protein inwardly rectifying potassium channel. These mutations disrupt the channel's selectivity filter, permitting abnormal sodium influx. We aimed to identify compounds that selectively activate mutant KCNJ5 channels. By further increasing sodium conductance, such compounds could induce lethal sodium influx in mutant adrenal cells, providing a targeted therapeutic strategy for primary aldosteronism caused by KCNJ5 mutations. METHODS:Six small molecules identified in our prior work as potential KCNJ5 agonists were evaluated. Their effects on cell viability, sodium influx, membrane potential, and steroidogenesis were assessed in 2-dimensional and 3-dimensional human adrenocortical cells, clone 15. RESULTS:Candidate agonists were tested for their ability to enhance adrenal cell death induced by overexpression of mutant KCNJ5. Compound 105 (C105; 2'-amino-6-chloro-1'-[2,4-difluorophenyl]-7-methyl-2,5'-dioxo-1,2,5',6',7',8'-hexahydro-1'H-spiro[indole-3,4'-quinoline]-3'-carbonitrile) increased mutant KCNJ5-induced cell death by 40% without affecting cells expressing wild-type KCNJ5. The toxic effect of C105 was abolished under low-sodium conditions. Inductively coupled plasma tandem mass spectrometry demonstrated a 25% increase in intracellular sodium after C105 treatment without significantly affecting potassium concentrations. Molecular docking indicated binding of C105 to the G-protein-binding site of KCNJ5, a key region involved in channel activation. These findings suggest that C105 promotes adrenal cell death through activation of mutant KCNJ5 and increased sodium conductance. CONCLUSIONS:C105 acts as a first-in-class mutant KCNJ5 agonist candidate and may enable pharmacological ablation of mutant cells in a subset of aldosterone-producing adenomas and familial hyperaldosteronism type III. These findings provide proof of concept for mutation-selective targeting of KCNJ5-driven primary aldosteronism.
BACKGROUND:Whether isolated diastolic hypertension (IDH) in young adults represents a benign, age-specific phenotype or confers increased cardiovascular disease risk remains uncertain. We assessed the associations between hypertension subtypes, IDH, isolated systolic hypertension, and systolic-diastolic hypertension, with atherosclerotic cardiovascular disease and heart failure. We also characterized longitudinal transitions in hypertension subtypes from young adulthood into later life. METHODS:Adults aged ≥18 years without cardiovascular disease were included from 4 US cohorts. Hypertension subtypes were defined using blood pressure thresholds of ≥130/80 mm Hg. Cox proportional hazards models were used to estimate the associations of hypertension subtypes with atherosclerotic cardiovascular disease and heart failure. RESULTS:Among 23 957 participants (mean age, 44.5 years, 42.5% were young adults aged 18-39 years, 45.1% were male), 2320 atherosclerotic cardiovascular disease and 1243 heart failure events occurred over a median follow-up of 17.2 years. Among young adults, the adjusted hazard ratios (95% CI) for atherosclerotic cardiovascular disease were 1.36 (95% CI, 1.11-1.68) for IDH, 1.54 (95% CI, 1.02-2.32) for isolated systolic hypertension, and 1.84 (95% CI, 1.46-2.32) for systolic-diastolic hypertension, compared with normotension. Corresponding hazard ratios for heart failure were 1.69 (95% CI, 1.24-2.31) for IDH, 1.92 (95% CI, 1.09-3.40) for isolated systolic hypertension, and 1.69 (95% CI, 1.17-2.43) for systolic-diastolic hypertension. Associations were consistent among adults aged ≥40 years. Among young adults with IDH, 29.8% remained with IDH, whereas 36.5% progressed to systolic-diastolic hypertension later in life. CONCLUSIONS:IDH in young adulthood represents an early marker of increased cardiovascular disease risk and a precursor to more adverse hypertension subtypes. These findings underscore the importance of early recognition, ongoing blood pressure monitoring, and guideline-concordant pharmacological treatment, when indicated, among young adults with IDH to reduce long-term cardiovascular disease risk.
BACKGROUND:T lymphocytes play a crucial role in the development of hypertension and associated end-organ damage. CD38 is a well-established surface marker for T-cell activation. However, clinical evidence linking CD38+ T cells, or other specific T-cell subsets, with blood pressure (BP) changes remains limited. We therefore sought to determine whether CD38+ T-cell abundance correlates with BP and whether anti-CD38 therapy influences BP in humans and mice. METHODS:We performed correlation analyses between peripheral immune cell counts and BP in 197 normotensive and 53 hypertensive subjects. The impact of CD38-targeted therapy on BP was evaluated in multiple myeloma patients (control, n=50; daratumumab, n=27). In addition, we used a murine model of angiotensin II-induced hypertension to characterize T-cell frequency and phenotype in the circulation and kidney by flow cytometry. RESULTS:Circulating CD38+ T-cell abundance was inversely correlated with BP in both normotensive and hypertensive subjects. This finding was recapitulated in hypertensive mice, which also showed concomitant accumulation of CD38+ T cells in the kidney. In patients, daratumumab-induced depletion of CD38+ cells reduced systolic BP by ≈10 mm Hg for 4 to 6 weeks. This BP-lowering effect was similarly observed in hypertensive mice given an antimurine CD38 antibody. CONCLUSIONS:Our data identify circulating CD38+ T cells as a novel immunologic biomarker that inversely correlates with BP, potentially reflecting T-cell transmigration during BP elevation.
BACKGROUND:The relationship between mean blood pressure (BP) and BP control remains uncertain, particularly the mean BP required to achieve BP control (<140/90 mm Hg) in most patients. This review assesses the association between mean BP and BP control using data from randomized clinical trials (RCTs). METHODS:Electronic literature databases were searched to identify individual RCTs (iRCTs) and cluster RCTs (cRCTs) that randomized adults to BP-lowering interventions and reported both mean BP at final follow-up visit (mean BP) and the proportion of participants achieving BP control at the final follow-up visit (BP control). RESULTS:A linear regression model was used to evaluate the association between mean BP and BP control. A total of 101 RCTs (65 iRCTs [57 201 participants] and 36 cRCTs [28 154 participants]) were included. Overall, mean systolic BP (SBP) of 120, 125, 130, and 135 mm Hg corresponded to BP control in 85%, 75%, 65% and 55% of the participants in iRCTs and 87%, 77%, 67%, 57% in cRCTs. Each 1 mm Hg reduction in mean SBP was associated with approximately a 2% increase in BP control (Pseudo-R2=78% for iRCTs; 76% for cRCTs). This association was consistent across BP-lowering drug classes, baseline SBP categories, and pretrial treatment status in iRCTs, and across country income levels and baseline SBP categories in cRCTs. A similar association was seen for DBP. CONCLUSIONS:An SBP below 125 mm Hg was associated with achieving BP control in ≈80% of patients. These findings can inform guideline recommendations, guide clinical management and shape hypertension control programs.
BACKGROUND:Assessment and treatment of orthostatic hypotension (OH) are recommended to prevent falls in older adults. However, the optimal timing of standing blood pressure (BP) assessments to identify clinically relevant OH remains unclear. METHODS:We measured 3 supine BP readings after 5 minutes of rest at 30-second intervals and 6 standing BP readings (timed at 0, 1, 2, 3, 4, and 5 minutes after standing) during the ARIC study (Atherosclerosis Risk in Communities) visit 10. OH was defined as a drop in BP (systolic ≥20 mm Hg or diastolic ≥10 mm Hg) on standing from the supine position. We quantified the prevalence and predictors of initial OH (immediately after standing), early OH (within 3 minutes), late OH (after 3 minutes), and sustained OH (all 6 minutes). We examined their associations with orthostatic symptoms and falls using logistic regression and negative binomial models, respectively. RESULTS:Of the 863 participants (mean age, 83.7 years), 41.3% had initial OH. Participants on antihypertensive medications had higher odds of all types of OH irrespective of controlled (<130/80 mm Hg) or uncontrolled (≥130/80 mm Hg) hypertension compared with those without hypertension (<130/80 mm Hg) and no antihypertensive use. Initial and early OH were strongly associated with orthostatic symptoms in the process of standing from the supine position (odds ratio, 2.34 [95% CI, 1.42-3.86]; odds ratio, 1.82 [95% CI, 1.11-2.98], respectively). Finally, participants with initial OH had higher fall rates (rate ratio, 1.45 [95% CI, 1.02-2.06]) than those without OH. CONCLUSIONS:Measuring BP within 3 minutes of standing, particularly the first BP measurement immediately after standing, may provide clinicians with important information on falls risk and orthostatic symptoms.
BACKGROUND: Thoracic aortic dissection (TAD) is a highly lethal disease without effective drug therapy. Guidelines recommend control of risk factors, particularly of causal hypertension. Antihypertensive drugs are diverse in mechanisms of action, but no randomized controlled trials have been undertaken to evaluate their efficacy and safety, and guide rational drug selection for this disease. METHODS: Antihypertensive drugs were evaluated in a 3-aminopropionitrile-induced mouse model of TAD. Pharmacovigilance analysis using the FDA Adverse Events Reporting System and Medical Information Mart for Intensive Care databases, along with a systematic meta-analysis of 32 studies, was performed to assess drug-associated risks in aortic diseases. Signaling pathways related to smooth muscle cell contractility, adhesion, and cytoskeleton stabilization were examined in human and mouse tissues. A chemogenetic mouse strain with smooth muscle cell-specific expression of the pharmacologically selective actuator module 4-serotonin type 3 receptor channel was generated to modulate Ca 2+ signaling. RESULTS: Here, we assessed 8 classes of antihypertensives in a mouse TAD disease model but unexpectedly observed that hydrochlorothiazide and minoxidil exacerbated the disease. Pharmacovigilance analysis linked diuretic use to an increased TAD-associated risk in patients. TAD pathogenesis and the harmful drug effects are attributable to blunted Ca 2+ -dependent smooth muscle cell contractility and adhesion. To this therapeutic end, we leveraged a chemogenetic Ca 2+ -permeable cation channel (pharmacologically selective actuator module 4-serotonin type 3 receptor) exclusively activated by the clinical drug varenicline. The humanized chemogenetic device boosted smooth muscle cell Ca 2+ signaling, potentiated the Ca 2+ -dependent cellular processes, and protected against TAD and the aggravated phenotype induced by hydrochlorothiazide/minoxidil. CONCLUSIONS: This study calls for pharmacovigilance of certain antihypertensives in TAD, and suggests that pharmacologically selective actuator module 4-serotonin type 3 receptor, as a viable means of tuning Ca 2+ signaling, holds translational potential for TAD therapy.
BACKGROUND: SIRT1 (sirtuin-1) regulates various cellular and metabolic processes in the vasculature. SIRT1 is an NAD + -dependent deacetylase that deacetylates transcription factors that control vascular inflammation and remodeling. Given that pathways regulated by SIRT1 are implicated in the pathophysiology of intracranial aneurysms, we hypothesized that activation and overexpression of SIRT1 prevent aneurysm rupture by suppressing vascular inflammation. METHODS: Intracranial aneurysms were induced in mice by systemic hypertension and a single intracisternal injection of elastase. We analyzed the expression of SIRT1 in human and mouse aneurysms. We investigated the role of SIRT1 in aneurysm rupture using genetic overexpression of SIRT1 and cell-specific deletion in the endothelial, vascular smooth muscle, and myeloid lineages. We administered a SIRT1 activator and a SIRT1 inhibitor to assess the rupture rate and mRNA expression in cerebral arteries. RESULTS: SIRT1 expression was significantly lower in intracranial aneurysm tissues than in control cerebral arteries in mice, with a similar trend in human aneurysms. Global overexpression of SIRT1 significantly decreased the rupture rate. Endothelial SIRT1 deletion increased the rupture rate, with no effect observed in other cell types. Inhibition of SIRT1 increased the rupture rate, whereas SIRT1 activation reduced the rupture rate and suppressed mRNA expression of proinflammatory cytokines in cerebral arteries. CONCLUSIONS: Our findings support a protective role of SIRT1 against intracranial aneurysm rupture in mice, with endothelial SIRT1 playing an important role in aneurysm stabilization. Pharmacological SIRT1 activation reduced aneurysm rupture and was associated with reduced vascular inflammation, providing a preclinical rationale for further investigation of SIRT1-related pathways.
BACKGROUND:Hypertension guidelines generally recommend uniform sodium restriction although determinants of salt sensitivity, or sodium-blood pressure responsiveness, remain incompletely quantified. We estimated the population sodium-blood pressure dose-response, identified clinical modifiers, quantified high salt sensitivity prevalence, and derived the number needed to restrict sodium intake to prevent 1 cardiovascular event across clinical strata. METHODS:PubMed, Excerpta Medica Database, and Cochrane were searched from inception to April 2025 for sodium intervention trials and observational studies. Blood pressure response was standardized per 50-mmol/d sodium difference. Random-effects meta-regression evaluated clinical modifiers. A highly salt-sensitive phenotype was defined a priori as a systolic blood pressure (SBP) decrease ≥3 mm Hg per 50-mmol/d reduction. RESULTS:We included 160 studies (255 estimates; n=16 443). Each 50-mmol/d higher urinary sodium excretion was associated with 1.76-mm Hg higher SBP (95% CI, 1.54-1.98). Age and baseline SBP were the strongest modifiers (0.41 mm Hg per 5 years; 0.23 mm Hg per 5 mm Hg). Salt-sensitive phenotype prevalence rose from 12.5% (age <40 years) to 56.5% (≥60 years) and from 16.3% (SBP <120 mm Hg) to 54.1% (≥130 mm Hg). Under a policy-relevant 100-mmol/d sodium reduction, number needed to restrict ranged from ≈1334 in younger, normotensive, lean individuals (age <60 years, SBP <130 mm Hg, and body mass index <25 kg/m2) to ≈87 in older adults with hypertension and elevated body mass index (age ≥60 years, SBP ≥130 mm Hg, and body mass index ≥25 kg/m2), a 15-fold gradient. CONCLUSIONS:Salt sensitivity varied across age, SBP, and body mass index strata. These findings suggest that routinely measured clinical characteristics may help identify populations with greater expected blood pressure response to sodium reduction.
This review discusses the implications of frameworks leveraging genetic admixture and multiomics data for advancing gene discovery in cardiovascular and kidney disease research. By broadening gene discovery efforts to additional populations that have a disproportionately high risk of disease and leveraging genetic diversity in admixed populations, studies can identify population-enriched risk variants that traditionally have been missed in genome-wide association studies. The use of multiomics approaches, including the transcriptome, proteome, and metabolome, advances a mechanistic understanding of disease beyond associations. As single-cell omics technologies continue to improve, their integration into gene discovery may help uncover cell-type-specific regulatory pathways and more precise biological contexts. The full potential of these approaches depends on sustained investment in diverse, well-characterized omics data sets, methodological innovation in multiancestry statistical approaches, and interdisciplinary collaboration bridging genomics, epidemiology, and clinical medicine. These efforts will need to be translated into clinically actionable insights, including ancestry-informed risk stratification and targeted therapeutics, to improve outcomes for cardiovascular and kidney diseases.
BACKGROUND:Primary aldosteronism (PA) is a common and treatable cause of hypertension, yet data on the durability of medical treatment response beyond the first year are limited. Using the PA medical treatment outcomes framework, we evaluated long-term biochemical and clinical outcomes and factors associated with treatment response. METHODS:We conducted an international, multicenter, observational cohort study across 27 centers on 4 continents. Adults with PA treated with mineralocorticoid receptor antagonists and/or epithelial sodium channel blockers between 2016 and 2021 were included if follow-up data were available at ≥12 months. Biochemical and clinical responses were classified as complete, partial, or absent using PA medical treatment outcomes criteria. Ordinal logistic regression identified determinants of a favorable treatment response. RESULTS:The cohort included 1292 patients (47.5% women, mean age 52 years) with a median follow-up of 34 months (interquartile range, 21-51). At ≥12 months, 58.3% achieved a complete biochemical response, and 20.8% achieved a complete clinical response, with only 5% showing no response. Determinants of a favorable biochemical response included lower aldosterone and lateralization index, and higher renin and potassium levels at baseline. In those taking spironolactone, a higher daily dose was also associated with a favorable biochemical response. Determinants of a favorable clinical response included female sex, lower body mass index, shorter duration of hypertension, and absence of hypertension-mediated organ damage. CONCLUSIONS:Targeted medical therapy for PA can deliver sustained biochemical and clinical benefits. Early disease detection and adequate dose titration are highly actionable determinants of long-term treatment success.
BACKGROUND:Although NLRP3 (NOD-like receptor family pyrin domain containing 3) inflammasome activation has been implicated in pressure overload-induced cardiac hypertrophy, inflammation, and heart failure, prior studies have focused primarily on cardiomyocytes and immune cells. The potential contribution of cardiac fibroblasts to NLRP3 inflammasome activation under pressure overload remains poorly defined. Here, we investigated the role of cardiac fibroblasts in NLRP3 inflammasome activation and sought to identify its key upstream regulator in the pressure-overloaded heart. METHODS:We analyzed single-cell transcriptomic data set of human and murine hearts, together with fibroblast-specific Nlrp3-knockout mice and S1pr2 loss- and gain-of-function mouse models. Transverse aortic constriction was used to induce pressure overload. RESULTS:We identified cardiac fibroblasts as the principal effectors of NLRP3 inflammasome activation under pressure overload. NLRP3 deficiency in fibroblasts markedly attenuated cardiac hypertrophy and inflammation under pressure overload. We further found that S1PR2 (sphingosine-1-phosphate receptor 2) is a critical upstream regulator of fibroblast NLRP3 inflammasome activation. Fibroblast-specific S1PR2 deletion suppressed inflammasome activation, mitigated hypertrophy, and preserved cardiac function, whereas S1PR2 overexpression in fibroblasts exacerbated these pathological changes under pressure overload. Further analyses revealed that S1PR2/ROCK (rho-associated coiled-coil-containing protein kinase) signaling augments DRP1 (dynamin-related protein 1)-dependent mitochondrial fission while suppressing Parkin-mediated mitophagy, thereby promoting mitochondrial damage and mitochondrial DNA leakage, which in turn culminate in NLRP3 inflammasome activation. CONCLUSIONS:This study provides in vivo evidence that cardiac fibroblasts constitute a major source of NLRP3 inflammasome activation in response to pressure overload. Fibroblast S1PR2 signaling links mitochondrial dysfunction to inflammasome activation, revealing a novel proinflammatory axis that exacerbates pressure overload-induced heart failure.
