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BioRxiv : the Preprint Server For... Jun 2024Salt sensitivity of blood pressure (SSBP) is an independent risk factor for cardiovascular morbidity and mortality, yet the etiology is poorly understood. We previously...
BACKGROUND
Salt sensitivity of blood pressure (SSBP) is an independent risk factor for cardiovascular morbidity and mortality, yet the etiology is poorly understood. We previously found that serum/glucocorticoid-regulated kinase 1 (SGK1) and epoxyeicosatrienoic acids (EETs) regulate epithelial sodium channel (ENaC)-dependent sodium entry into monocyte-derived antigen-presenting cells (APCs) and activation of NADPH oxidase, leading to the formation of isolevuglandins (IsoLGs) in SSBP. Whereas aldosterone via the mineralocorticoid receptor (MR) activates SGK1 leading to hypertension, our past findings indicate that levels of plasma aldosterone do not correlate with SSBP, and there is little to no MR expression in APCs. Thus, we hypothesized that cortisol acting via the glucocorticoid receptor (GR), not the MR in APCs mediates SGK1 actions to induce SSBP.
METHODS
We performed cellular indexing of transcriptomes and epitopes by sequencing (CITE-Seq) analysis on peripheral blood mononuclear cells of humans rigorously phenotyped for SSBP using an inpatient salt loading/depletion protocol to determine expression of MR, GR, and SGK1 in immune cells. In additional experiments, we performed bulk transcriptomic analysis on isolated human monocytes following treatment with high salt from a separate cohort. We then measured urine and plasma cortisol, cortisone, renin, and aldosterone. Subsequently, we measured the association of these hormones with changes in systolic, diastolic, mean arterial pressure and pulse pressure as well as immune cell activation via IsoLG formation.
RESULTS
We found that myeloid APCs predominantly express the GR and SGK1 with no expression of the MR. Expression of the GR in APCs increased after salt loading and decreased with salt depletion in salt-sensitive but not salt-resistant people and was associated with increased expression of . Moreover, we found that plasma and urine cortisol/cortisone but not aldosterone/renin correlated with SSBP and APCs activation via IsoLGs. We also found that cortisol negatively correlates with EETs.
CONCLUSION
Our findings suggest that renal cortisol signaling via the GR but not the MR in APCs contributes to SSBP via cortisol. Urine and plasma cortisol may provide an important currently unavailable feasible diagnostic tool for SSBP. Moreover, cortisol-GR-SGK1-ENaC signaling pathway may provide treatment options for SSBP.
NOVELTY AND RELEVANCE
Although salt sensitivity is a major risk factor for cardiovascular morbidity and mortality, the mechanisms underlying the salt sensitivity of blood pressure (SSBP) are poorly understood.High salt modifies glucocorticoid-receptor expression in antigen-presenting cells (APCs), suggesting a critical role of glucocorticoids in SSBP. Elevated glucocorticoid receptor (GR) expression compared to mineralocorticoid receptor (MR) expression in APCs provides evidence for a GR-dependent pathway to SSBP. Isolevuglandins (IsoLGs) increased in APCs after hydrocortisone treatment compared to aldosterone treatment, indicating that cortisol was the predominant driver of IsoLG production in these cells. Our studies suggest a mechanism for expression through GR activation by cortisol that differs from the currently accepted mechanism for SSBP pathogenesis. Although aldosterone has been used to study SSBP, there has been no consideration of cortisol as a major driver of the condition.Understanding alternative inflammatory pathways that affect SSBP may provide insights into the mechanism of SSBP and suggest a range of therapeutic targets.Our studies may provide a practical approach to understanding and treating salt-sensitive hypertension. Our findings firmly support a GR-dependent signaling pathway for activating SSBP via expression. A cortisol-driven mechanism could provide a practical approach for targeted treatments for salt-sensitive hypertension. Moreover, it could pave the way for a diagnostic approach.
PubMed: 38915603
DOI: 10.1101/2024.06.10.598374 -
Hypertension Research : Official... Jun 2024
PubMed: 38914705
DOI: 10.1038/s41440-024-01757-w -
Journal of Cardiology Jun 2024Improving congestion with diuretic therapy is crucial in the treatment of heart failure (HF). However, despite the use of loop diuretics, diuresis may be inadequate and... (Review)
Review
Improving congestion with diuretic therapy is crucial in the treatment of heart failure (HF). However, despite the use of loop diuretics, diuresis may be inadequate and congestion persists, which is known as diuretic resistance. Diuretic resistance and residual congestion are associated with a higher risk of rehospitalization and mortality. Causes of diuretic resistance in HF include diuretic pharmacokinetic changes, renal hemodynamic perturbations, neurohumoral activations, renal tubular remodeling, and use of nephrotoxic drugs as well as patient comorbidities. Combination diuretic therapy (CDT) has been advocated for the treatment of diuretic resistance. Thiazides, acetazolamides, tolvaptan, mineralocorticoid receptor antagonist, and sodium-glucose co-transporter-2 inhibitors are among the candidates, but none of these treatments has yet demonstrated significant diuretic efficacy or improved prognosis. At present, it is essential to identify and treat the causes of diuretic resistance in individual patients and to use CDT based on a better understanding of the characteristics of each drug to achieve adequate diuresis. Further research is needed to effectively assess and manage diuretic resistance and ultimately improve patient outcomes.
PubMed: 38914279
DOI: 10.1016/j.jjcc.2024.06.005 -
Blood Pressure Dec 2024Objective Real-life management of patients with hypertension and chronic kidney disease (CKD) among European Society of Hypertension Excellence Centres (ESH-ECs) is...
Management of patients with hypertension and chronic kidney disease referred to Hypertension Excellence Centres among 27 countries. On behalf of the European Society of Hypertension Working Group on Hypertension and the Kidney.
Objective Real-life management of patients with hypertension and chronic kidney disease (CKD) among European Society of Hypertension Excellence Centres (ESH-ECs) is unclear : we aimed to investigate it. Methods A survey was conducted in 2023. The questionnaire contained 64 questions asking ESH-ECs representatives to estimate how patients with CKD are managed. Results Overall, 88 ESH-ECS representatives from 27 countries participated. According to the responders, renin-angiotensin system (RAS) blockers, calcium-channel blockers and thiazides were often added when these medications were lacking in CKD patients, but physicians were more prone to initiate RAS blockers (90% [interquartile range: 70-95%]) than MRA (20% [10-30%]), SGLT2i (30% [20-50%]) or (GLP1-RA (10% [5-15%]). Despite treatment optimisation, 30% of responders indicated that hypertension remained uncontrolled (30% (15-40%) vs 18% [10%-25%]) in CKD and CKD patients, respectively). Hyperkalemia was the most frequent barrier to initiate RAS blockers, and dosage reduction was considered in 45% of responders when kalaemia was 5.5-5.9 mmol/L. Conclusions RAS blockers are initiated in most ESH-ECS in CKD patients, but MRA and SGLT2i initiations are less frequent. Hyperkalemia was the main barrier for initiation or adequate dosing of RAS blockade, and RAS blockers' dosage reduction was the usual management.
Topics: Humans; Renal Insufficiency, Chronic; Hypertension; Europe; Antihypertensive Agents; Male; Surveys and Questionnaires; Female; Middle Aged; Calcium Channel Blockers; Societies, Medical; Angiotensin Receptor Antagonists
PubMed: 38910347
DOI: 10.1080/08037051.2024.2368800 -
American Journal of Cardiovascular... Jun 2024The 2021 European Society of Cardiology (ESC) Guidelines recommend the use of four different classes of drugs for heart failure with reduced ejection fraction (HFrEF):...
INTRODUCTION
The 2021 European Society of Cardiology (ESC) Guidelines recommend the use of four different classes of drugs for heart failure with reduced ejection fraction (HFrEF): beta blockers (BB), sodium-glucose cotransporter-2 inhibitors (SGLT2i), angiotensin receptor/neprilysin inhibitor (ARNI), and mineralocorticoid receptor antagonists (MRAs). Moreover, the 2023 ESC updated Guidelines suggest an intensive strategy of initiation and rapid up-titration of evidence-based treatment before discharge, based on trials not using the four-pillars. We hypothesized that an early concomitantly administration and up-titration of four-pillars, compared with a conventional stepwise approach, may impact the vulnerable phase after hospitalization owing to HF.
METHODS
This prospective, single center, observational study included consecutive in-hospital patients with HFrEF. After performing propensity score matching, they were divided according to treatment strategy into group 1 (G1), with predischarge start of all four-pillars, with their up-titration within 1 month, and group 2 (G2) with the pre Guidelines update stepwise four-pillars introduction. HF hospitalization, cardiovascular (CV) death, and the composite of both were evaluated between the two groups at 6-month follow-up.
RESULTS
The study included a total of 278 patients who completed 6-month follow-up (139 for both groups). There were no differences in terms of baseline features between the two groups. At survival analysis, HF hospitalization risk was significantly lower in G1 compared with G2 (p < 0.001), while no significant differences were observed regarding CV death (p = 0.642) or the composite of CV death and HF hospitalization (p = 0.135).
CONCLUSIONS
In our real-world population, patients with HF treated with a predischarge and simultaneous use of four-pillars showed a reduced risk of HF hospitalization during the vulnerable phase after discharge, compared with a conventional stepwise approach.
PubMed: 38909334
DOI: 10.1007/s40256-024-00660-6 -
American Journal of Cardiovascular... Jun 2024Increasing knowledge of the processes leading to heart failure (HF) has allowed significant developments in therapies for HF over the past few decades. Despite the... (Review)
Review
Increasing knowledge of the processes leading to heart failure (HF) has allowed significant developments in therapies for HF over the past few decades. Despite the evolution of HF treatment, it still places a large burden on patients and health care systems across the world.We used clinicaltrials.gov to gather information about clinical trials as of August 2023 studying pharmacotherapy for HF. We included interventional trials that were "active, not recruiting", "recruiting", or looking for participants but "not yet recruiting". In total, 119 studies met our criteria of ongoing clinical trials studying novel as well as currently approved HF pharmacotherapies. The major interventions were novel medications/already approved medications for other diseases 29 % (34 trials), sodium-glucose co-transporter inhibitors 21 % (25 trials), angiotensin receptor blocker-neprilysin inhibitors 10 % (12 trials), diuretics 14 % (17 trials) and mineralocorticoid receptor antagonists 5 % (6 trials). Ongoing research will aid in reducing the impact of HF and we summarize clinical trials leading the way to better HF treatment in this review.
PubMed: 38907865
DOI: 10.1007/s40256-024-00658-0 -
Frontiers in Pediatrics 2024Hyponatremia is one of the most prevalent water-electrolyte disturbances encountered in clinical practice in pediatrics and can arise from various conditions. However,...
INTRODUCTION
Hyponatremia is one of the most prevalent water-electrolyte disturbances encountered in clinical practice in pediatrics and can arise from various conditions. However, there are limited reports on hyponatremia in hospitalized infants. The objective of this study was to provide an overview of the incidence, etiologies, and clinical characteristics of hyponatremia in hospitalized babies (from birth to 3 years old) at a tertiary hospital.
METHOD
Computer records of all hospitalized babies (from birth to 3 years old) with hyponatremia were extracted from the First Affiliated Hospital of Guangxi Medical University's clinical databases.
RESULTS
801 patients from 39,019 hospital admissions were found to have hyponatremia and the overall prevalence of this condition was 2.05% in babies. Patients with hyponatremia due to aldosterone signaling abnormalities, neurological disorders, and liver diseases exhibited more severe outcomes than those with other etiologies.
CONCLUSIONS
Various conditions can result in hyponatremia in hospitalized babies. Aldosterone signaling abnormalities were not that uncommon and it could lead to severe hyponatremia in babies.
PubMed: 38903768
DOI: 10.3389/fped.2024.1338404 -
Minerva Medica Jun 2024Managing non-cardiac comorbidities in heart failure (HF) requires a tailored approach that addresses each patient's specific conditions and needs. Regular communication... (Review)
Review
Managing non-cardiac comorbidities in heart failure (HF) requires a tailored approach that addresses each patient's specific conditions and needs. Regular communication and coordination among healthcare providers is crucial to providing the best possible care for these patients. Poorly controlled hypertension contributes to left ventricular remodeling and diastolic dysfunction, emphasizing the importance of optimal blood pressure control while avoiding adverse effects. Among HF patients with diabetes, SGLT2 inhibitors and mineralocorticoid receptor antagonists have shown promise in reducing HF-related morbidity and mortality. Chronic kidney disease exacerbates HF and vice versa, forming the vicious cardiorenal syndrome, so disease-modifying therapies should be maintained in HF patients with comorbid CKD, even with transient changes in kidney function. Anemia in HF patients may be multifactorial, and there is growing evidence for the benefit of intravenous iron supplementation in HF patients with iron deficiency with or without anemia. Obesity, although a risk factor for HF, paradoxically offers a better prognosis once HF is established, though developing treatment strategies may improve symptoms and cardiac performance. In HF patients with stroke and atrial fibrillation, anticoagulation therapy is recommended. Among HF patients with sleep-disordered breathing, continuous positive airway pressure may improve sleep quality. Chronic obstructive pulmonary disease often coexists with HF, and many patients can tolerate cardioselective beta-blockers. Cancer patients with comorbid HF require careful consideration of cardiotoxicity risks associated with cancer therapies. Depression is underdiagnosed in HF patients and significantly impacts prognosis. Cognitive impairment is prevalent in HF patients and impacts their self-care and overall quality of life.
Topics: Humans; Heart Failure; Pulmonary Disease, Chronic Obstructive; Comorbidity; Renal Insufficiency, Chronic; Hypertension; Sleep Apnea Syndromes; Neoplasms; Obesity; Anemia; Stroke; Atrial Fibrillation; Anticoagulants; Mineralocorticoid Receptor Antagonists; Cardio-Renal Syndrome
PubMed: 38899946
DOI: 10.23736/S0026-4806.24.09070-0 -
BMJ (Clinical Research Ed.) Jun 2024Resistant hypertension is defined as blood pressure that remains above the therapeutic goal despite concurrent use of at least three antihypertensive agents of different... (Review)
Review
Resistant hypertension is defined as blood pressure that remains above the therapeutic goal despite concurrent use of at least three antihypertensive agents of different classes, including a diuretic, with all agents administered at maximum or maximally tolerated doses. Resistant hypertension is also diagnosed if blood pressure control requires four or more antihypertensive drugs. Assessment requires the exclusion of apparent treatment resistant hypertension, which is most often the result of non-adherence to treatment. Resistant hypertension is associated with major cardiovascular events in the short and long term, including heart failure, ischemic heart disease, stroke, and renal failure. Guidelines from several professional organizations recommend lifestyle modification and antihypertensive drugs. Medications typically include an angiotensin converting enzyme inhibitor or angiotensin receptor blocker, a calcium channel blocker, and a long acting thiazide-type/like diuretic; if a fourth drug is needed, evidence supports addition of a mineralocorticoid receptor antagonist. After a long pause since 2007 when the last antihypertensive class was approved, several novel agents are now under active development. Some of these may provide potent blood pressure lowering in broad groups of patients, such as aldosterone synthase inhibitors and dual endothelin receptor antagonists, whereas others may provide benefit by allowing treatment of resistant hypertension in special populations, such as non-steroidal mineralocorticoid receptor antagonists in patients with chronic kidney disease. Several device based approaches have been tested, with renal denervation being the best supported and only approved interventional device treatment for resistant hypertension.
Topics: Humans; Hypertension; Antihypertensive Agents; Drug Resistance; Drug Therapy, Combination; Calcium Channel Blockers; Blood Pressure
PubMed: 38897628
DOI: 10.1136/bmj-2023-079108 -
The Egyptian Heart Journal : (EHJ) :... Jun 2024Amyloidosis, particularly wild-type transthyretin amyloidosis (ATTRwt), is an increasingly recognized cause of heart failure with preserved ejection fraction in the...
BACKGROUND
Amyloidosis, particularly wild-type transthyretin amyloidosis (ATTRwt), is an increasingly recognized cause of heart failure with preserved ejection fraction in the aging population. The complexity of managing ATTRwt in older patients underscores the necessity for individualized treatment approaches, yet clinical guidelines are lacking. This case report contributes to the understanding of ATTRwt management in the elderly, emphasizing the intricacies of medication tolerance and therapeutic decision-making.
CASE PRESENTATION
An 83-year-old Korean man with a history of hypertension presented with dyspnea and peripheral edema. Investigations including electrocardiography, transthoracic echocardiography, cardiac magnetic resonance, and Technetium pyrophosphate scintigraphy led to a diagnosis of ATTRwt cardiac amyloidosis. Initial management with heart failure medications, including an angiotensin-converting enzyme inhibitor, diuretic, and mineralocorticoid receptor antagonist, was modified due to evolving clinical presentations, such as hypotension and onset of atrial fibrillation. Challenges included intolerance to beta-blockers and bleeding complications from direct oral anticoagulant therapy. The patient's treatment journey highlighted the need for personalized management strategies in older ATTRwt patients.
CONCLUSIONS
This case illustrates the challenges in diagnosing and managing ATTRwt amyloidosis in the elderly, particularly the complexities in medication management due to the patient's age, comorbid conditions, and side effects. It underscores the importance of a tailored approach in managing ATTRwt in older populations and highlights the need for ongoing research and development of treatment strategies tailored to this demographic.
PubMed: 38888709
DOI: 10.1186/s43044-024-00507-0