Predicting chronic responses to calcium channel blockade with a virtual population of African Americans with hypertensive chronic kidney disease.

Chronic kidney disease (CKD) is associated with the progressive loss of functional nephrons and hypertension (HTN). Clinical studies demonstrate calcium channel blocker (CCB) therapy mitigates the decline in renal function in humans with essential HTN. However, there are few long-term clinical studies that determine the impact of CCBs in patients with hypertensive CKD.

CD8 T cells promote heart failure progression in mice with preexisting left ventricular dysfunction.

Introduction: Even under the standard medical care, patients with left ventricular (LV) failure or heart failure (HF) often progress to pulmonary hypertension and right ventricular (RV) hypertrophy. We previously showed that inflammation and regulatory T cells (Tregs) modulate HF progression in mice with preexisting LV failure. The main objective of this study is to determine the role of CD8 T cells in modulating LV failure and the consequent pulmonary inflammation and RV hypertrophy in mice with preexisting LV failure.

Revisiting sex as a biological variable in hypertension research.

Half of adults in the United States have hypertension as defined by clinical practice guidelines. Interestingly, women are generally more likely to be aware of their hypertension and have their blood pressure controlled with treatment compared with men, yet hypertension-related mortality is greater in women. This may reflect the fact that the female sex remains underrepresented in clinical and basic science studies investigating the effectiveness of therapies and the mechanisms controlling blood pressure.

High selenium diet attenuates pressure overload-induced cardiopulmonary oxidative stress, inflammation, and heart failure.

Selenium (Se) deficiency is associated with the development of Keshan disease, a cardiomyopathy associated with massive cardiac immune cell infiltration that can lead to heart failure (HF). The purpose of this study was to determine whether high Se diet can attenuate systolic overload-induced cardiopulmonary inflammation and HF. Briefly, transverse aortic constriction (TAC)-induced cardiopulmonary oxidative stress, inflammation, left ventricular (LV) dysfunction, and pulmonary remodeling were determined in male mice fed with either high Se diet or normal Se diet.

Endothelial specific prolyl hydroxylase domain-containing protein 2 deficiency attenuates aging-related obesity and exercise intolerance.

Obesity and exercise intolerance greatly reduce the life quality of older people. Prolyl hydroxylase domain-containing protein 2 (PHD2) is an important enzyme in modulating hypoxia-inducible factor-alpha (HIF) protein. Using vascular endothelial cell-specific PHD2 gene knockout (PHD2 ECKO) mice, we investigated the role of endothelial PHD2 in aging-related obesity and exercise capacity.

Modeling the renoprotective mechanisms of SGLT2 inhibition in hypertensive chronic kidney disease.

Sodium-glucose cotransporter (SGLT)-2 inhibitors have recently been approved for chronic kidney disease (CKD) based on their ability to lower proteinuria and slow CKD progression independent of diabetes status. In diabetic renal disease, modulation of tubuloglomerular feedback (TGF) leading to lower intraglomerular pressure has been postulated as one of the mechanisms of renal protection with SGLT2 inhibition; however, this mechanism has not been sufficiently explored in non-diabetic CKD. We hypothesized that SGLT2 inhibition exerts renoprotection in CKD through increasing TGF despite normoglycemia.

Don't sweat the small stuff: skin mechanisms of sodium homeostasis and associations with long-term blood pressure.

Despite the overwhelming evidence that the kidney is the principal regulator of chronic blood pressure though the ability to sense pressure and adjust blood volume accordingly, recent clinical and preclinical evidence suggests that skin clearance of Na+ through sweat significantly contributes to long-term blood pressure and risk of hypertension. Evidence indicates that changes in skin Na+ content negatively associate with renal function, and factors that influence the concentration of Na+ in sweat are affected by major regulators of Na+ excretion by the kidney such as angiotensin and aldosterone. In addition, known regulatory mechanisms that regulate the amount of sweat produced do not include changes in Na+ intake or blood volume.

Retrospective analysis of SGLT2 inhibitors in heart failure with preserved ejection fraction.

Aims: Heart failure (HF) is one of the leading causes of cardiovascular morbidity and mortality. HF with preserved ejection fraction (HFpEF), or diastolic failure, accounts for half of all HF cases and differs from HF with reduced ejection fraction (HFrEF). Patients with HFpEF are typically older, female, and commonly seen with chronic kidney disease (CKD), one of the leading independent risk factors for mortality in these patients.

Modeling the physiological roles of the heart and kidney in heart failure with preserved ejection fraction during baroreflex activation therapy.

Heart failure (HF) is a leading cause of death and is increasing in prevalence. Unfortunately, therapies that have been efficacious in patients with HF with reduced ejection fraction (HFrEF) have not convincingly shown a reduction in cardiovascular mortality in patients with HF with preserved ejection fraction (HFpEF). It is thought that high sympathetic nerve activity (SNA) in the heart plays a role in HF progression.

Physiological Mechanisms of Hypertension and Cardiovascular Disease in End-Stage Kidney Disease.

Purpose Of Review: In this article, we summarize recent advances in understanding hypertension and cardiovascular disease in patients with end-stage kidney disease.

Recent Findings: Factors such as anemia, valvular and vascular calcification, vasoconstrictors, uremic toxins, hypoglycemia, carbamylated proteins, oxidative stress, and inflammation have all been associated with the progression of cardiovascular disease in end-stage kidney disease but the causality of these mechanisms has not been proven. The high risk of cardiovascular mortality has not improved as in the general population despite many advancements in cardiovascular care over the last two decades.

Endothelin antagonism reduces hemoglobin A1c in patients with pulmonary hypertension.

Our lab recently reported that the blockade of endothelin-1 (ET-1) receptors attenuates insulin resistance in obese mice; therefore, we hypothesized that patients taking ET-1 receptor antagonists (ERAs) will have improved glycemic control. University of Mississippi Medical Center (2013-2020) electronic health record (EPIC) data were extracted from patients ≥18 years old with a clinical diagnosis of pulmonary hypertension (Food and Drug Administration indication for ERA use) and at least two clinical visits within 2 years. Patients prescribed ERAs ( = 11) were similar in age (61 ± 14 years vs.

Antihypertensive effects of immunosuppressive therapy in autoimmune disease.

Systemic lupus erythematosus (SLE) is a chronic multisystem autoimmune disorder that primarily affects women of childbearing age. While immune system dysfunction has been implicated in the development of hypertension (HTN) in SLE, the effect of immunomodulatory drugs on blood pressure (BP) control in SLE patients is unknown. In the present study, we hypothesized that first-line immunomodulatory therapies prescribed to SLE patients would have a beneficial impact on BP.

In silico trial of baroreflex activation therapy for the treatment of obesity-induced hypertension.

Clinical trials evaluating the efficacy of chronic electrical stimulation of the carotid baroreflex for the treatment of hypertension (HTN) are ongoing. However, the mechanisms by which this device lowers blood pressure (BP) are unclear, and it is uncertain which patients are most likely to receive clinical benefit. Mathematical modeling provides the ability to analyze complicated interrelated effects across multiple physiological systems.

Questioning the renoprotective role of L-type calcium channel blockers in chronic kidney disease using physiological modeling.

Chronic kidney disease (CKD) is characterized by the progressive functional loss of nephrons and hypertension (HTN). Some antihypertensive regimens attenuate the progression of CKD (blockers of the renin-angiotensin system). Although studies have suggested that calcium channel blocker (CCB) therapy mitigates the decline in renal function in humans with essential HTN, there are few long-term clinical studies that have determined the impact of CCBs in patients with hypertensive CKD.

Corrigendum: Racial and Sex Differences in the Response to First-Line Antihypertensive Therapy.

[This corrects the article DOI: 10.3389/fcvm.2020.

Racial and Sex Differences in the Response to First-Line Antihypertensive Therapy.

As compared to whites, the black population develops hypertension (HTN) at an earlier age, has a greater frequency and severity of HTN, and has poorer control of blood pressure (BP). Traditional practices and treatment efforts have had minor impact on these disparities, with over a 2-fold higher death rate currently for blacks as compared to whites. The University of Mississippi Medical Center (UMC) is located in the southeastern US and the Stroke Belt, which has higher rates of HTN and related diseases as compared to the rest of the country.

Physiological Modeling and Simulation-Validation, Credibility, and Application.

In this review, we discuss the science of model validation as it applies to physiological modeling. There is widespread disagreement and ambiguity about what constitutes model validity. In areas in which models affect real-world decision-making, including within the clinic, in regulatory science, or in the design and engineering of novel therapeutics, this question is of critical importance.

Preeminent role of the cardiorenal axis in the antihypertensive response to an arteriovenous fistula: an in silico analysis.

Percutaneous creation of a small central arteriovenous (AV) fistula is currently being evaluated for the treatment of uncontrolled hypertension (HT). Although the mechanisms that contribute to the antihypertensive effects of the fistula are unclear, investigators have speculated that chronic blood pressure (BP) lowering may be due to ) reduced total peripheral resistance (TPR), ) increased secretion of atrial natriuretic peptide (ANP), and/or ) suppression of renal sympathetic nerve activity (RSNA). We used an established integrative mathematical model of human physiology to investigate these possibilities from baseline conditions that mimic sympathetic overactivity and impaired renal function in patients with resistant HT.

Sex-specific responses to mineralocorticoid receptor antagonism in hypertensive African American males and females.

Background: African Americans (AA) develop hypertension (HTN) at an earlier age, have a greater frequency and severity of HTN, and greater prevalence of uncontrolled HTN as compared to the white population. Mineralocorticoid antagonists have been shown to be very effective in treating uncontrolled HTN in both AA and white patients, but sex-specific responses are unclear.

Methods: We evaluated the sex-specific impact of mineralocorticoid antagonism in an AA population.

Early treatment with GLP-1 after severe trauma preserves renal function in obese Zucker rats.

Early posttrauma hyperglycemia (EPTH) is correlated with later adverse outcomes, including acute kidney injury (AKI). Controlling EPTH in the prehospital setting is difficult because of the variability in the ideal insulin dosage and the potential risk of hypoglycemia, especially in those with confounding medical comorbidities of obesity and insulin resistance. Glucagon-like peptide-1 (GLP-1) controls glucose levels in a glucose-dependent manner and is a current target in antidiabetic therapy.

Role of the heart in blood pressure lowering during chronic baroreflex activation: insight from an in silico analysis.

Electrical stimulation of the baroreflex chronically suppresses sympathetic activity and arterial pressure and is currently being evaluated for the treatment of resistant hypertension. The antihypertensive effects of baroreflex activation are often attributed to renal sympathoinhibition. However, baroreflex activation also decreases heart rate, and robust blood pressure lowering occurs even after renal denervation.

Simulating a virtual population's sensitivity to salt and uninephrectomy.

Salt sensitivity, with or without concomitant hypertension, is associated with increased mortality. Reduced functional renal mass plays an important role in causing salt-sensitive hypertension for many individuals. Factors that are important in the condition of decreased renal mass and how they affect blood pressure (BP) or salt sensitivity are unclear.

Physiologic Mechanisms of Water and Electrolyte Disturbances After Transsphenoidal Pituitary Surgery.

Background: Disturbances in water and electrolyte homeostasis are common after transsphenoidal surgery. These disorders are variable and unpredictable, increasing patient risk and complicating postsurgical treatment. Clinically, it is generally accepted that damage to the pituitary is the cause, but the mechanisms behind the response variability and underlying pathophysiology remain unknown.

Mechanisms of blood pressure salt sensitivity: new insights from mathematical modeling.

Mathematical modeling is an important tool for understanding quantitative relationships among components of complex physiological systems and for testing competing hypotheses. We used HumMod, a large physiological model, to test hypotheses of blood pressure (BP) salt sensitivity. Systemic hemodynamics, renal, and neurohormonal responses to chronic changes in salt intake were examined during normal renal function, fixed low or high plasma angiotensin II (ANG II) levels, bilateral renal artery stenosis, increased renal sympathetic nerve activity (RSNA), and decreased nephron numbers.