Pathophysiology Of Hypertension Research Articles

Multiple urinary peptides are associated with hypertension: a link to molecular pathophysiology.

Hypertension is a common condition worldwide; however, its underlying mechanisms remain largely unknown. This study aimed to identify urinary peptides associated with hypertension to further explore the relevant molecular pathophysiology. Peptidome data from 2876 individuals without end-organ damage were retrieved from the Human Urinary Proteome Database, belonging to general population (discovery) or type 2 diabetic (validation) cohorts. Participants were divided based on systolic blood pressure (SBP) and diastolic BP (DBP) into hypertensive (SBP ≥140 mmHg and/or DBP ≥90 mmHg) and normotensive (SBP <120 mmHg and DBP <80 mmHg, without antihypertensive treatment) groups. Differences in peptide abundance between the two groups were confirmed using an external cohort ( n = 420) of participants without end-organ damage, matched for age, BMI, eGFR, sex, and the presence of diabetes. Furthermore, the association of the peptides with BP as a continuous variable was investigated. The findings were compared with peptide biomarkers of chronic diseases and bioinformatic analyses were conducted to highlight the underlying molecular mechanisms. Between hypertensive and normotensive individuals, 96 (mostly COL1A1 and COL3A1) peptides were found to be significantly different in both the discovery (adjusted) and validation (nominal significance) cohorts, with consistent regulation. Of these, 83 were consistently regulated in the matched cohort. A weak, yet significant, association between their abundance and standardized BP was also observed. Hypertension is associated with an altered urinary peptide profile with evident differential regulation of collagen-derived peptides. Peptides related to vascular calcification and sodium regulation were also affected. Whether these modifications reflect the pathophysiology of hypertension and/or early subclinical organ damage requires further investigation.

Markers of Vascular Dysfunction in Hypertension.

Hypertension is a modifiable cardiovascular risk factor and displays a rapidly growing incidence due to aging and the acquisition of an unhealthy lifestyle. Hypertension is linked to the development of target organ damage in several vascular beds such as coronary arteries, peripheral, cerebral, and renal arteries. Besides, along with the presence of other cardiovascular risk factors, it aggravates vascular dysfunction due to the aging process. The mechanisms of vascular dysfunction in hypertension are complex and involve excessive salt intake and water retention, activation of neurohormonal systems, induction of endothelial dysfunction of large arteries and microcirculation, development of arterial stiffness, and complex interactions with cellular pathways of inflammation, oxidative stress, and thrombosis. The extent of vascular dysfunction in patients with hypertension can be assessed by evaluating endothelial function, measuring arterial stiffness, and testing the levels of circulating biomarkers of oxidative stress, pro-inflammatory cytokines, and thrombosis. Assessing these markers in subjects with and without hypertension could aid in identifying those at risk of vascular damage and improving risk prediction for future cardiovascular events. While several lifestyle and pharmacological therapies have shown promise in addressing vascular dysfunction in hypertension, none of these biomarkers have been established as an independent risk factor or treatment target. Therefore, in this article, we review the literature on the evidence that exists regarding the role of vascular dysfunction in the pathophysiology, diagnosis, progression, and treatment of hypertension, highlighting the lack of conclusive evidence in this field.

Sex and circadian regulation of metabolic demands in the rat kidney: A modeling analysis.

Renal hemodynamics, renal transporter expression levels, and urine excretion exhibit circadian variations. Disruption of these diurnal patterns is associated with the pathophysiology of hypertension and chronic kidney disease. Renal hemodynamics determines oxygen delivery, whereas renal transport and metabolism determines oxygen consumption; the balance between them yields renal oxygenation which also demonstrates 24-h periodicity. Another notable modulator of kidney function is sex, which has impacts on renal hemodynamics and transport function that are regulated by as well as independent of the circadian clock. The goal of this study was to investigate the diurnal and sexual variations in renal oxygen consumption and oxygenation. For this purpose, we developed computational models of rat kidney function that represent sexual dimorphism and circadian variation in renal hemodynamics and transporter activities. Model simulations predicted substantial differences in tubular Na+ transport and oxygen consumption among different nephron segments. We also simulated the effect of loop diuretics, which are used in the treatment of renal hypoxia, on medullary oxygen tension. Our model predicted a significantly higher effect of loop diuretics on medullary oxygenation in female rats compared to male rats and when administered during the active phase.

Rare Adverse Effect of a Commonly Used Drug in Chronic Kidney Disease

Chronic kidney disease (CKD) and hypertension can lead to each other. Majority of the patients with CKD have hypertension.Sympathetic overactivity has been suggested as one of the important etiologies of hypertension in CKD patients. Clonidine isused as a central sympatholytic to control hypertension in CKD patients. Drug-induced sialadenitis has been reported withmultiple drugs including antihypertensives. We report a case of clonidine-induced sialadenitis, which has been rarely seendespite the widespread use of this drug among CKD patients requiring multiple antihypertensive drugs.

The Construction and Meaning of Race Within Hypertension Guidelines: A Systematic Scoping Review.

Professional society guidelines are evidence-based recommendations intended to promote standardized care and improve health outcomes. Amid increased recognition of the role racism plays in shaping inequitable healthcare delivery, many researchers and practitioners have critiqued existing guidelines, particularly those that include race-based recommendations. Critiques highlight how racism influences the evidence that guidelines are based on and its interpretation. However, few have used a systematic methodology to examine race-based recommendations. This review examines hypertension guidelines, a condition affecting nearly half of all adults in the United States (US), to understand how guidelines reference and develop recommendations related to race. A systematic scoping review of all professional guidelines on the management of essential hypertension published between 1977 and 2022 to examine the use and meaning of race categories. Of the 37 guidelines that met the inclusion criteria, we identified a total of 990 mentions of race categories.Black and African/African American were the predominant race categories referred to in guidelines (n = 409). Guideline authors used race in five key domains: describing the prevalence or etiology of hypertension; characterizing prior hypertension studies; describing hypertension interventions; social risk and social determinants of health; the complexity of race. Guideline authors largely used race categories as biological rather than social constructions. None of the guidelines discussed racism and the role it plays in perpetuating hypertension inequities. Hypertension guidelines largely refer to race as a distinct and natural category rather than confront the longstanding history of racism within and beyond the medical system.Normalizing race as a biological rather than social construct fails to address racism as a key determinant driving inequities in cardiovascular health. These changes are necessary to produce meaningful structural solutions that advance equity in hypertension education, research, and care delivery.

The RICA-2 registry: design and baseline characteristics of the first 1,000 patients

Background and objectiveHeart failure (HF) is a syndrome of epidemic proportions and one of the main reasons for hospital admission. Patient registries provide real-world clinical practice information which is complementary to clinical trials. RICA-2 is a registry of the Spanish Society of Internal Medicine. Its main goal is to know the clinical and epidemiological characteristics and prognostic factors of patients with HF treated in Internal Medicine Departments. The objective of this study is to present the design of the RICA-2, the baseline characteristics of the first 1000 patients included and their comparison with those of the historical cohort of the RICA registry. MethodsObservational, multicentre and prospective study of patients with HF with the following inclusion criteria: age equal to or greater than 18 years old, diagnosis of HF according to the European Guidelines, indistinct inclusion in decompensation or stable phase, of patients with de novo HF or chronic HF, regardless of left ventricular ejection fraction, aetiology and comorbidities. ResultsRICA-2 patients have advanced age (83 years old) and 51% are women. The comorbidity burden is higher than in the RICA registry (5 points in the Charlson comorbidity index), with predominating chronic decompensated HF (74%), hypertensive aetiology (39%) and preserved ejection fraction (52%). Most patients are pre-frail or vulnerable and are at risk of malnutrition. ConclusionThe RICA-2 represents a contemporary cohort of patients that will provide us with clinical, epidemiological and prognostic information on patients with acute and chronic HF treated in Internal Medicine.

Clinical Spectrum of Acute Post-streptococcal Glomerulonephritis in Children: A Kashmir Experience.

Background In the pediatric population, acute post-streptococcal glomerulonephritis (PSGN) is a common glomerular etiology of hematuria and acute hypertension leading to hospitalization. We conducted this study to know the clinical profile and occurrence of acute PSGN in patients presenting with features of acute nephritic syndrome. Methods This prospective observational study was conducted on children aged between two and 18 years, presenting with clinical features of acute glomerular nephritis (AGN). After due ethical considerations, all eligible patients were enrolled and underwent detailed clinical assessment, laboratory, and imaging evaluation, followed by protocolized treatment. Relevant data were collected and analyzed to reach valid results. Results Out of 60 patients with AGN, PSGN was found in 83.3% of the patients (50/60). The age group under five years wasthe most commonly involved, with a male/female ratio of 1.6:1. Around half of the studied patients were from the lower middle class, and 40 (80%) were from rural backgrounds. Facial puffiness was the most common clinical presentation, seen in 45 (90%) patients. Hypocomplementemia and proteinuria were seen in all PSGN patients. Pyoderma was the most common preceding infection, seen in 38 (76%) patients, followed by pharyngitis. Acute kidney injury (AKI) was the most common complication, seen in 12 (24%) patients. Complete resolution of the signs and symptoms was seen in 37 (74%) patients at the time of discharge, which increased to 47 (94%) patients at six months post discharge. Conclusion PSGN stands to be the most common cause of pediatric AGN. The population under five years of age, with a past history of pyoderma, is more predisposed to PSGN. The potential for the occurrence of AKI and other life-threatening complications is high, for which early diagnosis and institution of proper treatment would be very beneficial.

Pathophysiology and therapeutic options for cirrhotic portal hypertension.

Portal hypertension represents the primary non-neoplastic complication of liver cirrhosis and has life-threatening consequences, such as oesophageal variceal bleeding, ascites, and hepatic encephalopathy. Portal hypertension occurs due to increased resistance of the cirrhotic liver vasculature to portal blood flow and is further aggravated by the hyperdynamic circulatory syndrome. Existing knowledge indicates that the profibrogenic phenotype acquired by sinusoidal cells is the initial factor leading to increased hepatic vascular tone and fibrosis, which cause increased vascular resistance and portal hypertension. Data also suggest that the phenotype of hepatic cells could be further impaired due to the altered mechanical properties of the cirrhotic liver itself, creating a deleterious cycle that worsens portal hypertension in the advanced stages of liver disease. In this Review, we discuss recent discoveries in the pathophysiology and treatment of cirrhotic portal hypertension, a condition with few pharmacological treatment options.

Pregnancy-Induced Hypertension Pathophysiology and Contemporary Management Strategies: A Narrative Review.

In the case of PIH, the history is the story of gradually developing awareness and the gradual formation of requisite knowledge. The development of the sphygmomanometer, or blood pressure cuff, in the late 1700s, provided the basis for modern systematic blood pressure reporting for Gravid patients. In the following years and over a few decades, the relationship between high blood pressure and these complications, such as preeclampsia and eclampsia, became clearer. The hypertensive disease was categorized by the American Committee on Maternal Welfare in 1952, which included PIH, chronic hypertension, and preeclampsia. Today, attention is being paid to the identification of such factors, the search for ways to enhance the treatment of diseases, methods for their diagnosis, and the enhancement of pregnancy outcomes. Pregnancy can cause high blood pressure in two of the following ways: preeclampsia and gestational hypertension. These conditions are both part of something called pregnancy-induced hypertension (PIH). In the world, most problems for moms and babies during pregnancy come from PIH. To help both mom and baby, we need to know a lot about what causes it, how to manage it, and how to watch the baby carefully. Aspects like immune responses, the environment, and genes all mix to cause PIH. They make the placenta not work right. When the cells that help the placenta grow don't do their job well, when blood vessels are stiff, when there's too much stress on the body, or when there's not a good balance of chemicals that help build blood vessels, things can get bad. Blood vessels all over the body squeeze tight, blood flow goes down, and blood pressure goes up. That can make a lot of organs stop working right and stop the baby from healthy growth. Various studies concluded that PIH severely limits the blood flow to the placenta and thus contributes to reduced fetal growth. It showed that compared to other hospitals, women who experience PIH are more likely to give birth early before the baby is ready, that is, before 37 weeks, and may cause further health complications to the baby. This normally makes the offspring have low birth weight and exposes them to many complications in infancy and the future in case they are born to mothers with PIH. In severe cases, PIH may lead to the death of the infant either by stillbirth or immediately after birth. The researchers have noted several predisposing factors to PIH, which include histories of elevated blood pressure, diabetes, being overweight or obese, and having a family history of PIH. Educating women about the presence of PIH and its causes can help them consult health facilities early, thus helping leaders in achieving better pregnancy results.

The Pathophysiology, Prognosis and Treatment of Hypertension in Females from Pregnancy to Post-menopause: A Review

Abstract Purpose of Review We summarise the physiological changes and risk factors for hypertension in females, potential sex-specific management approaches, and long-term prognosis. Key Findings Pregnancy and menopause are two key phases of the life cycle where females undergo significant biological and physical changes, making them more prone to developing hypertension. Gestational hypertension occurs from changes in maternal cardiac output, kidney function, metabolism, or placental vasculature, with one in ten experiencing pregnancy complications such as intrauterine growth restriction and delivery complications such as premature birth. Post-menopausal hypertension occurs as the protective effects of oestrogen are reduced and the sympathetic nervous system becomes over-activated with ageing. Increasing evidence suggests that post-menopausal females with high blood pressure (BP) experience greater risk of cardiovascular events at lower BP thresholds, and greater vulnerability to treatment-related adverse effects. Summary Hypertension is a key risk factor for cardiovascular disease in females. Current BP treatment guidelines and recommendations are similar for both sexes, without addressing sex-specific factors. Future investigations into ideal diagnostic thresholds, BP control targets and treatment regimens in females are needed.

An in Vitro triple screen model for human mineralocorticoid receptor activity

The mineralocorticoid receptor (MR, NR3C2) mediates ion and water homeostasis in epithelial cells of the distal nephron and other tissues. Aldosterone, the prototypical mineralocorticoid, regulates electrolyte and fluid balance. Cortisol binds to MR with equal affinity to aldosterone, but many MR-expressing tissues inactivate cortisol to cortisone via 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2). Dysregulated MR activation contributes to direct cardiovascular tissue insults. Besides aldosterone and cortisol, a variety of MR agonists and/or HSD11B2 inhibitors are putative players in the pathophysiology of low-renin hypertension (LRH), and cardiovascular and metabolic pathology. We developed an in vitro human MR (hMR) model, to facilitate screening for MR agonists, antagonists, and HSD11B2 inhibitors. The CV1 monkey kidney cells were transduced with lentivirus to stably express hMR and an MR-responsive gaussia luciferase gene. Clonal populations of MR-expressing cells (CV1-MRluc) were further transduced to express HSD11B2 (CV1-MRluc-HSD11B2). CV1-MRluc and CV1-MRluc-HSD11B2 cells were treated with aldosterone, cortisol, 11-deoxycorticosterone (DOC), 18-hydroxycorticosterone (18OHB), 18-hydroxycortisol (18OHF), 18-oxocortisol (18oxoF), progesterone, or 17-hydroxyprogesterone (17OHP). In CV1-MRLuc cells, aldosterone and DOC displayed similar potency (EC50: 0.45 nM and 0.30 nM) and maximal response (31- and 23-fold increase from baseline) on hMR; 18oxoF and 18OHB displayed lower potency (19.6 nM and 56.0 nM, respectively) but similar maximal hMR activation (25- and 27-fold increase, respectively); cortisol and corticosterone exhibited higher maximal responses (73- and 52-fold, respectively); 18OHF showed no MR activation. Progesterone and 17OHP inhibited aldosterone-mediated MR activation. In the MRluc-HSD11B2 model, the EC50 of cortisol for MR activation increased from 20 nM (CV1-MRLuc) to ∼2000 nM, while the EC50 for aldosterone remained unchanged. The addition of 18β-glycyrrhetinic acid (18β-GA), a HSD11B2 inhibitor, restored the potency of cortisol back to ∼70 nM in CV1-hMRLuc-HSD11B2 cells. Together, these two cell models will facilitate the discovery of novel MR-modulators, informing MR-mediated pathophysiology mechanisms and drug development efforts.

Causal association between blood metabolites and risk of hypertension: a Mendelian randomization study.

Previous studies have indicated a strong link between blood metabolites and hypertension, however the causality of metabolites and hypertension is unknown. Two-sample Mendelian randomization (MR) analysis was performed to assess the causal relationship between 486 blood metabolites and essential hypertension (EHT). Blood metabolite GWAS data was utilized as the exposure, with EHT GWAS data as the outcome. To further verify the results, another different source of EHT GWAS data was repeatedly analyzed. The major MR analytic approach used to determine causality was inverse variance weighted (IVW), with MR-Egger, Weighted Median, and MR-PRESSO models serving as supplements. We used the Cochran Q test to examine heterogeneity. Horizontal pleiotropy was examined using MR-Egger intercept and MR-PRESSO global test. The MR Steiger test confirmed the causal relationship between blood metabolites and EHT. In this study, nine blood metabolites associated with EHT were preliminarily identified by MR analysis, including four known metabolites (N-acetylornithine, X-12510-2-aminooctanoic acid, creatine, hexadecanedioate) and five unknown metabolites. Then another source of EHT GWAS data was repeatedly analyzed for further verification, and two overlapped metabolites (N-acetylornithine, X-12510-2-aminooctanoic acid) were found. There was a negative correlation between N-acetylornithine and EHT (OR = 0.987, 95% CI = 0.980-0.993, P = 1.01 × 10-4), Cochran's Q test suggested there was no heterogeneity (Q = 31.7586, P = 0.1331), MR-Egger intercept and MR-PRESSO global test suggested there was no horizontal pleiotropy (P > 0.05), Leave-one-out analysis indicated that no single single-nucleotide polymorphism (SNP) had a significant effect on the results, and MR Steiger test confirmed that the direction of causality was correct (P < 0.001). There was a negative correlation between X-12510-2-aminooctanoic acid and EHT (OR = 0.982, 95% CI = 0.972-0.993, P = 0.0017), and there was no evidence of heterogeneity or pleiotropy in multiple sensitivity analyses. The study discovered some blood metabolites causally linked to EHT, which might lead to new understandings of the pathophysiology of hypertension.

Prevalence and Characteristics of Low-renin Hypertension in a Primary Care Population.

Low-renin hypertension is an underrecognized subtype of hypertension with specific treatment options. This study aims to identify the prevalence in primary care and to compare patient characteristics to those with normal-renin hypertension and primary aldosteronism (PA). In a cohort study, patients with treatment-naïve hypertension were screened for PA with plasma aldosterone and direct renin concentrations. Patients with an elevated aldosterone-to-renin ratio [≥70 pmol/mU (≥2.5 ng/dL:mU/L)] underwent confirmatory testing. All screened patients were then classified as having (1) normal-renin hypertension, (2) low-renin hypertension (direct renin concentration <10mU/L (plasma renin activity ∼<1 ng/mL/hour) and not meeting the criteria for PA), or (3) confirmed PA. Of the 261 patients, 69 (26.4%) had low-renin hypertension, 136 (51.9%) had normal renin hypertension, and 47 (18.0%) had PA. Patients with low-renin hypertension were older and more likely to be female compared to normal-renin hypertension (57.1 ± 12.8 years vs 51.8 ± 14.0 years, P < .05 and 68.1% vs 49.3%, P < .05, respectively) but similar to PA (53.5 ± 11.5 years and 55.3%). However, in an adjusted binomial logistic regression, there was no association between increasing age or sex and low-renin hypertension. The median aldosterone concentration was lower compared to patients with normal-renin hypertension and PA: 279 pmol/L (216-355) vs 320 pmol/L (231-472), P < .05 and 419 pmol/L (360-530), P < .001. At least a quarter of treatment-naïve hypertensive patients in primary care had a low direct renin concentration but did not meet the criteria for PA. Patient characteristics were similar, aside from a lower aldosterone concentration compared to patients with normal-renin hypertension and PA. Further research is needed to understand the underlying pathophysiology of low-renin hypertension and the optimal first-line treatment.

Controversies in the pathophysiology of arterial hypertension.

Introduction: Purinergic receptors actively participate in the renal alterations in high blood pressure. The elevation of ATP in the renal interstitium activates purinergic receptors, constituting a fundamental pathway in the generation and persistence of arterial hypertension. Objective of the review: This article is a narrative review that aims to show the importance of new concepts in the pathophysiology of arterial hypertension. Essential points of the review: Purinergic receptors are ATP receptors; the more significant the ATP, the greater the purinergic receptors. Elevated ATP concentrations alter fundamental mechanisms related to blood pressure control, such as the pressure natriuresis mechanism and renal sodium excretion, the regulation of glomerular filtration, and the tubuloglomerular feedback mechanism. The alteration of these mechanisms decreases urinary sodium excretion. Whether influenced by genetic alterations or induced by vasoconstrictor peptides, a decrease in renal function and tubulointerstitial injury occur before the glomerulus is injured. The interaction between angiotensin II and purinergic receptors favors the progression of kidney damage. Conclusion: Kidney damage in high blood pressure is critical, so efforts should be made to control hypertension to prevent the progression of kidney damage that leads to kidney failure. To obtain better blood pressure control, developing purinergic receptor antagonists for clinical use is possible.

Natriuretic peptide system in hypertension: Current understandings of its regulation, targeted therapies and future challenges

The natriuretic peptide system (NPS) is the key driving force of the heart's endocrine function. Recent developments in NPS-targeted therapies have been found promising and effective against cardiovascular diseases, including hypertension. Notably, after discovering crosstalk between NPS and the renin-angiotensin-aldosterone system (RAAS), various combinations such as neprilysin/angiotensin II receptor type 1 AT1 receptor inhibitors and neprilysin/renin inhibitors have been preclinically and clinically tested against various cardiac complications. However, the therapeutic effects of such combinations on the pathophysiology of hypertension are poorly understood. Furthermore, the complicated phenomena underlying NPS regulation and function, particularly in hypertension, are still unexplored. Mounting evidence suggests that numerous regulatory mechanisms modulate the expression of NPS, which can be used as potential targets against hypertension and other cardiovascular diseases. Therefore, this review will specifically focus on epigenetic and other regulators of NPS, identifying prospective regulators that might serve as new therapeutic targets for hypertension. More importantly, it will shed light on recent developments in NPS-targeted therapies, such as M-atrial peptides, and their latest combinations with RAAS modulators, such as S086 and sacubitril-aliskiren. These insights will aid in the development of effective therapies to break the vicious cycle of high blood pressure during hypertension, ultimately addressing the expanding global heart failure pandemic.

A Lifelike guided journey through the pathophysiology of pulmonary hypertension—from measured metabolites to the mechanism of action of drugs

IntroductionPulmonary hypertension (PH) is a pathological condition that affects approximately 1% of the population. The prognosis for many patients is poor, even after treatment. Our knowledge about the pathophysiological mechanisms that cause or are involved in the progression of PH is incomplete. Additionally, the mechanism of action of many drugs used to treat pulmonary hypertension, including sotatercept, requires elucidation.MethodsUsing our graph-powered knowledge mining software Lifelike in combination with a very small patient metabolite data set, we demonstrate how we derive detailed mechanistic hypotheses on the mechanisms of PH pathophysiology and clinical drugs.ResultsIn PH patients, the concentration of hypoxanthine, 12(S)-HETE, glutamic acid, and sphingosine 1 phosphate is significantly higher, while the concentration of L-arginine and L-histidine is lower than in healthy controls. Using the graph-based data analysis, gene ontology, and semantic association capabilities of Lifelike, led us to connect the differentially expressed metabolites with G-protein signaling and SRC. Then, we associated SRC with IL6 signaling. Subsequently, we found associations that connect SRC, and IL6 to activin and BMP signaling. Lastly, we analyzed the mechanisms of action of several existing and novel pharmacological treatments for PH. Lifelike elucidated the interplay between G-protein, IL6, activin, and BMP signaling. Those pathways regulate hallmark pathophysiological processes of PH, including vasoconstriction, endothelial barrier function, cell proliferation, and apoptosis.DiscussionThe results highlight the importance of SRC, ERK1, AKT, and MLC activity in PH. The molecular pathways affected by existing and novel treatments for PH also converge on these molecules. Importantly, sotatercept affects SRC, ERK1, AKT, and MLC simultaneously. The present study shows the power of mining knowledge graphs using Lifelike’s diverse set of data analytics functionalities for developing knowledge-driven hypotheses on PH pathophysiological and drug mechanisms and their interactions. We believe that Lifelike and our presented approach will be valuable for future mechanistic studies of PH, other diseases, and drugs.

Immunological insights into hypertension: unraveling triggers and potential therapeutic avenues.

Hypertension remains the leading cause of morbidity and mortality worldwide. Despite its prevalence, the development of novel antihypertensive therapies has only recently accelerated, with novel agents not yet commercialized, leaving a substantial proportion of individuals resistant to existing treatments. The intricate pathophysiology of hypertension is now understood to involve chronic low-grade inflammation, which places the immune system in the spotlight as a potential target for new therapeutics. This review explores the factors that initiate and sustain an immune response in hypertension, offering insights into potential targets for new treatments. Several factors contribute to immune activation in hypertension, including diet and damage-associated molecular pattern (DAMP) generation. Diets rich in fat or sodium can promote inflammation by inducing intestinal barrier dysfunction and triggering salt-sensitive receptors in T cells and dendritic cells. DAMPs, such as extracellular adenosine triphosphate and heat-shock protein 70, are released during episodes of increased blood pressure, contributing to immune cell activation and inflammation. Unconventional innate-like γδ T cells contribute to initiating and maintaining an immune response through their potential involvement in antigen presentation and regulating cytokine-mediated responses. Immunologic memory, sustained through the formation of effector memory T cells after exposure to hypertensive insults, likely contributes to maintaining an immune response in hypertension. When exposed to hypertensive insults, these memory cells are rapidly activated and contribute to elevated blood pressure and end-organ damage. Evidence from human hypertension, although limited, supports the relevance of distinct immune pathways in hypertension, and highlights the potential of targeted immune interventions in human hypertension. Diet and acute bouts of high blood pressure result in the release of dietary triggers, neoantigens, and damage-associated molecular patterns (DAMPs), which promote immune system activation. Elements such as lipopolysaccharides (LPS), sodium, heat-shock protein (HSP)70, extracellular adenosine triphosphate (eATP), and growth arrest-specific 6 (GAS6) promote activation of innate immune cells such as dendritic cells (DCs) and monocytes (Mo) through their respective receptors (toll-like receptor [TLR]4, amiloride-sensitive epithelial sodium channel [ENaC], TLR2/4, P2X7 receptor [P2RX7], and Axl) leading to costimulatory molecule expression and interleukin (IL)-1β and IL-23 production. The neoantigens HSP70 and isolevuglandins (IsoLGs) are presented to T cells by DCs and possibly γδ T cells, triggering T cell activation, IL-17 and interferon (IFN)-γ production, and the formation of T effector memory (TEM) cells in the kidney, perivascular adipose tissue, bone marrow, and spleen. Exposure of TEM cells to their cognate antigen or previous activating stimuli causes these cells rapid expansion and activation. Cumulatively, this inflammatory state contributes to hypertension and end-organ damage. The figure was created using images from smart.servier.com and is licensed under a Creative Commons Attribution 4.0 license (CC BY 4.0).

Etiologies of Splenic Venous Hypertension: A Review.

Splenic venous hypertension or left-sided portal hypertension is a rare condition caused by an obstruction of the splenic vein. Usually, it presents with upper gastrointestinal bleeding in the absence of liver disease. Etiologies can be classified based on the mechanism of development of splenic vein hypertension: compression, stenosis, inflammation, thrombosis, and surgically decreased splenic venous flow. Diagnosis is established by various imaging modalities and should be suspected in patients with gastric varices in the absence of esophageal varices, splenomegaly, or cirrhosis. The management and prognosis vary depending on the underlying etiology but generally involve reducing splenic venous pressure. The aim of this review was to summarize the etiologies of splenic venous hypertension according to the mechanism of development.

Revisiting resistant hypertension in kidney disease.

As compared to controlled or uncontrolled hypertension, resistant hypertension in patients with chronic kidney disease (CKD) poses a significantly increased healthcare burden due to greater target end-organ damage including cardiovascular disease and CKD progression. Patients with CKD have two to three times higher risk of developing resistant hypertension. True resistant hypertension needs to be distinguished from apparent treatment resistant hypertension (aTRH); however, it is usually not possible in epidemiological studies. Moreover, impact of contemporary guidelines changes in the target blood pressure (BP) goal to less than 130/80 mmHg remains to be determined. Up to half of patients with CKD meet aTRH criteria using 2017 ACC/AHA target BP less than 130/80 mmHg. Excess sodium retention in extracellular and tissue compartment remains the cornerstone cause of resistance to the treatment in CKD. Maximizing and optimizing the diuretic regimen in addition to dietary sodium restriction plays a critical role in these patients. Management requires a trustworthy provider-patient relationship facilitating identification and intervention for the barriers restricting the uptake of lifestyle modifications and medications. Recently, renal denervation has been approved and many other novel agents are on the horizon for treatment of true resistant hypertension associated with CKD. This review discusses the latest in the pathophysiology, definition, identification and treatment strategies of resistant hypertension in individuals with CKD. Further investigations are required to identify the prevalence, future implication and treatment outcome data for true resistant hypertension associated with CKD.

Noninvasive Pressure-Volume Loops Predict Major Adverse Cardiac Events in Heart Failure With Reduced Ejection Fraction

BackgroundHeart failure with reduced ejection fraction (HFrEF) is characterized by ventricular remodeling and impaired myocardial energetics. Left ventricular pressure-volume (PV) loop analysis can be performed noninvasively using cardiovascular magnetic resonance (CMR) imaging to assess cardiac thermodynamic efficiency. ObjectivesThe aim of the study was to investigate whether noninvasive PV loop parameters, derived from CMR, could predict major adverse cardiac events (MACE) in HFrEF patients. MethodsPV loop parameters (stroke work, ventricular efficiency, external power, contractility, and energy per ejected volume) were computed from CMR cine images and brachial blood pressure. The primary endpoint was MACE (cardiovascular death, heart failure (HF) hospitalization, myocardial infarction, revascularization, ventricular tachycardia/fibrillation, heart transplantation, or left ventricular assist device implantation within 5 years). Associations between PV loop parameters and MACE were evaluated using multivariable Cox regression. ResultsA total of 164 HFrEF patients (left ventricular ejection fraction ≤40%, age 63 [IQR: 55-70] years, 79% male) who underwent clinical CMR examination between 2004 and 2014 were included. Eighty-eight patients (54%) experienced at least 1 MACE after an average of 2.8 years. Unadjusted models demonstrated a significant association between MACE and all PV loop parameters (P < 0.05 for all), HF etiology (P < 0.001), left ventricular ejection fraction (P = 0.003), global longitudinal strain (P < 0.001), and N-terminal prohormone of brain natriuretic peptide level (P = 0.001). In the multivariable Cox regression analysis adjusted for age, sex, hypertension, diabetes, and HF etiology, ventricular efficiency was associated with MACE (HR: 1.04, 95% CI: 1.01-1.08, per-% decrease, P = 0.01). ConclusionsVentricular efficiency, derived from noninvasive PV loop analysis from standard CMR scans, is associated with MACE in patients with HFrEF.