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Article ; Online: A quantitative systems pharmacology model of plasma potassium regulation by the kidney and aldosterone.

Maddah, Erfan / Hallow, K Melissa

Journal of pharmacokinetics and pharmacodynamics

2022 Volume 49, Issue 4, Page(s) 471–486

Abstract: Plasma potassium regulation within a narrow range is vital for life. The risk for hyperkalemia increases when kidney function is impaired and with therapeutic interventions such as mineralocorticoid receptor antagonists (MRAs). The kidney maintains ... ...

Abstract	Plasma potassium regulation within a narrow range is vital for life. The risk for hyperkalemia increases when kidney function is impaired and with therapeutic interventions such as mineralocorticoid receptor antagonists (MRAs). The kidney maintains potassium homeostasis by matching potassium intake and excretion, in part through the action of aldosterone. A mechanistic mathematical model was developed and used to investigate the effect of renal impairment and MRAs on plasma potassium levels. The model describes renal potassium filtration, reabsorption, and secretion along the nephron; potassium-aldosterone regulatory feedbacks; whole body potassium balance; and the pharmacologic effects of MRAs. The model was calibrated by fitting (1) the plasma potassium and aldosterone response to potassium infusion in humans on high/low potassium diets, and (2) the acute potassium excretion response to spironolactone. The model was validated by predicting steady-state plasma potassium with sustained spironolactone treatment in hyperaldosteronism patients. The model was then used to demonstrate that (1) declining renal function alone has a small effect on plasma potassium for GFR > 30 ml/min, but an increasing effect as GFR approaches end stage renal disease (GFR ~ 15 ml/min) (2) the effect of increasing potassium intake has minimal effect at normal GFRs but increasing effect on plasma potassium as GFR declines, and 3) MRAs have a minor effect on plasma potassium when GFR is normal, but cause larger increases as GFR falls below 60 ml/min. This model provides a quantitative framework for investigating integrated impacts of diseases and therapies in this complex system.
MeSH term(s)	Aldosterone/pharmacology ; Humans ; Kidney/physiology ; Mineralocorticoid Receptor Antagonists/pharmacology ; Mineralocorticoid Receptor Antagonists/therapeutic use ; Network Pharmacology ; Potassium/pharmacology ; Spironolactone/pharmacology ; Spironolactone/therapeutic use
Chemical Substances	Mineralocorticoid Receptor Antagonists ; Spironolactone (27O7W4T232) ; Aldosterone (4964P6T9RB) ; Potassium (RWP5GA015D)
Language	English
Publishing date	2022-07-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2041601-5
ISSN	1573-8744 ; 1567-567X
ISSN (online)	1573-8744
ISSN	1567-567X
DOI	10.1007/s10928-022-09815-x
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Article: Quantifying the integrated physiological effects of endothelin-1 on cardiovascular and renal function in healthy subjects: a mathematical modeling analysis.

Yu, Hongtao / Greasley, Peter / Lambers-Heerspink, Hiddo / Boulton, David W / Hamrén, Bengt / Hallow, K Melissa

Frontiers in pharmacology

2024 Volume 15, Page(s) 1332394

Abstract: Endothelin-1 (ET-1) is a potent vasoconstrictor with strong anti-natriuretic and anti-diuretic effects. While many experimental studies have elucidated the mechanisms of ET-1 through its two receptors, ... ...

Abstract	Endothelin-1 (ET-1) is a potent vasoconstrictor with strong anti-natriuretic and anti-diuretic effects. While many experimental studies have elucidated the mechanisms of ET-1 through its two receptors, ET
Language	English
Publishing date	2024-04-05
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2587355-6
ISSN	1663-9812
ISSN	1663-9812
DOI	10.3389/fphar.2024.1332394
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Article ; Online: Understanding heterogeneous mechanisms of heart failure with preserved ejection fraction through cardiorenal mathematical modeling.

Basu, Sanchita / Yu, Hongtao / Murrow, Jonathan R / Hallow, K Melissa

PLoS computational biology

2023 Volume 19, Issue 11, Page(s) e1011598

Abstract: In contrast to heart failure (HF) with reduced ejection fraction (HFrEF), effective interventions for HF with preserved ejection fraction (HFpEF) have proven elusive, in part because it is a heterogeneous syndrome with incompletely understood ... ...

Abstract	In contrast to heart failure (HF) with reduced ejection fraction (HFrEF), effective interventions for HF with preserved ejection fraction (HFpEF) have proven elusive, in part because it is a heterogeneous syndrome with incompletely understood pathophysiology. This study utilized mathematical modeling to evaluate mechanisms distinguishing HFpEF and HFrEF. HF was defined as a state of chronically elevated left ventricle end diastolic pressure (LVEDP > 20mmHg). First, using a previously developed cardiorenal model, sensitivities of LVEDP to potential contributing mechanisms of HFpEF, including increased myocardial, arterial, or venous stiffness, slowed ventricular relaxation, reduced LV contractility, hypertension, or reduced venous capacitance, were evaluated. Elevated LV stiffness was identified as the most sensitive factor. Large LV stiffness increases alone, or milder increases combined with either decreased LV contractility, increased arterial stiffness, or hypertension, could increase LVEDP into the HF range without reducing EF. We then evaluated effects of these mechanisms on mechanical signals of cardiac outward remodeling, and tested the ability to maintain stable EF (as opposed to progressive EF decline) under two remodeling assumptions: LV passive stress-driven vs. strain-driven remodeling. While elevated LV stiffness increased LVEDP and LV wall stress, it mitigated wall strain rise for a given LVEDP. This suggests that if LV strain drives outward remodeling, a stiffer myocardium will experience less strain and less outward dilatation when additional factors such as impaired contractility, hypertension, or arterial stiffening exacerbate LVEDP, allowing EF to remain normal even at high filling pressures. Thus, HFpEF heterogeneity may result from a range of different pathologic mechanisms occurring in an already stiffened myocardium. Together, these simulations further support LV stiffening as a critical mechanism contributing to elevated cardiac filling pressures; support LV passive strain as the outward dilatation signal; offer an explanation for HFpEF heterogeneity; and provide a mechanistic explanation distinguishing between HFpEF and HFrEF.
MeSH term(s)	Humans ; Heart Failure ; Stroke Volume/physiology ; Heart ; Myocardium/pathology ; Hypertension/complications
Language	English
Publishing date	2023-11-13
Publishing country	United States
Document type	Journal Article
ZDB-ID	2193340-6
ISSN	1553-7358 ; 1553-734X
ISSN (online)	1553-7358
ISSN	1553-734X
DOI	10.1371/journal.pcbi.1011598
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Article ; Online: Cardiac and renal function interactions in heart failure with reduced ejection fraction: A mathematical modeling analysis.

Yu, Hongtao / Basu, Sanchita / Hallow, K Melissa

PLoS computational biology

2020 Volume 16, Issue 8, Page(s) e1008074

Abstract: Congestive heart failure is characterized by suppressed cardiac output and arterial filling pressure, leading to renal retention of salt and water, contributing to further volume overload. Mathematical modeling provides a means to investigate the ... ...

Abstract	Congestive heart failure is characterized by suppressed cardiac output and arterial filling pressure, leading to renal retention of salt and water, contributing to further volume overload. Mathematical modeling provides a means to investigate the integrated function and dysfunction of heart and kidney in heart failure. This study updates our previously reported integrated model of cardiac and renal functions to account for the fluid exchange between the blood and interstitium across the capillary membrane, allowing the simulation of edema. A state of heart failure with reduced ejection fraction (HF-rEF) was then produced by altering cardiac parameters reflecting cardiac injury and cardiovascular disease, including heart contractility, myocyte hypertrophy, arterial stiffness, and systemic resistance. After matching baseline characteristics of the SOLVD clinical study, parameters governing rates of cardiac remodeling were calibrated to describe the progression of cardiac hemodynamic variables observed over one year in the placebo arm of the SOLVD clinical study. The model was then validated by reproducing improvements in cardiac function in the enalapril arm of SOLVD. The model was then applied to prospectively predict the response to the sodium-glucose co-transporter 2 (SGLT2) inhibitor dapagliflozin, which has been shown to reduce heart failure events in HF-rEF patients in the recent DAPAHF clinical trial by incompletely understood mechanisms. The simulations predict that dapagliflozin slows cardiac remodeling by reducing preload on the heart, and relieves congestion by clearing interstitial fluid without excessively reducing blood volume. This provides a quantitative mechanistic explanation for the observed benefits of SGLT2i in HF-rEF. The model also provides a tool for further investigation of heart failure drug therapies.
MeSH term(s)	Benzhydryl Compounds/therapeutic use ; Cardiomegaly/physiopathology ; Extracellular Fluid/physiology ; Glucosides/therapeutic use ; Heart/physiopathology ; Heart Failure/drug therapy ; Heart Failure/physiopathology ; Hemodynamics/physiology ; Humans ; Kidney/physiopathology ; Models, Cardiovascular ; Myocytes, Cardiac/physiology ; Sodium-Glucose Transporter 2 Inhibitors/therapeutic use ; Stroke Volume/physiology
Chemical Substances	Benzhydryl Compounds ; Glucosides ; Sodium-Glucose Transporter 2 Inhibitors ; dapagliflozin (1ULL0QJ8UC)
Language	English
Publishing date	2020-08-17
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2193340-6
ISSN	1553-7358 ; 1553-734X
ISSN (online)	1553-7358
ISSN	1553-734X
DOI	10.1371/journal.pcbi.1008074
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Article: Cardiorenal Systems Modeling: Left Ventricular Hypertrophy and Differential Effects of Antihypertensive Therapies on Hypertrophy Regression.

Hallow, K Melissa / Van Brackle, Charles H / Anjum, Sommer / Ermakov, Sergey

Frontiers in physiology

2021 Volume 12, Page(s) 679930

Abstract: Cardiac and renal function are inextricably connected through both hemodynamic and neurohormonal mechanisms, and the interaction between these organ systems plays an important role in adaptive and pathophysiologic remodeling of the heart, as well as in ... ...

Abstract	Cardiac and renal function are inextricably connected through both hemodynamic and neurohormonal mechanisms, and the interaction between these organ systems plays an important role in adaptive and pathophysiologic remodeling of the heart, as well as in the response to renally acting therapies. Insufficient understanding of the integrative function or dysfunction of these physiological systems has led to many examples of unexpected or incompletely understood clinical trial results. Mathematical models of heart and kidney physiology have long been used to better understand the function of these organs, but an integrated model of renal function and cardiac function and cardiac remodeling has not yet been published. Here we describe an integrated cardiorenal model that couples existing cardiac and renal models, and expands them to simulate cardiac remodeling in response to pressure and volume overload, as well as hypertrophy regression in response to angiotensin receptor blockers and beta-blockers. The model is able to reproduce different patterns of hypertrophy in response to pressure and volume overload. We show that increases in myocyte diameter are adaptive in pressure overload not only because it normalizes wall shear stress, as others have shown before, but also because it limits excess volume accumulation and further elevation of cardiac stresses by maintaining cardiac output and renal sodium and water balance. The model also reproduces the clinically observed larger LV mass reduction with angiotensin receptor blockers than with beta blockers. We further provide a mechanistic explanation for this difference by showing that heart rate lowering with beta blockers limits the reduction in peak systolic wall stress (a key signal for myocyte hypertrophy) relative to ARBs.
Language	English
Publishing date	2021-06-16
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2564217-0
ISSN	1664-042X
ISSN	1664-042X
DOI	10.3389/fphys.2021.679930
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Article ; Online: A Quantitative Systems Physiology Model of Renal Function and Blood Pressure Regulation: Application in Salt-Sensitive Hypertension.

Hallow, K M / Gebremichael, Y

CPT: pharmacometrics & systems pharmacology

2017 Volume 6, Issue 6, Page(s) 393–400

Abstract: Salt-sensitivity (SS) refers to changes in blood pressure in response to changes in sodium intake. SS individuals are at greater risk for developing kidney disease, and also respond differently to antihypertensive therapies compared to salt-resistant (SR) ...

Abstract	Salt-sensitivity (SS) refers to changes in blood pressure in response to changes in sodium intake. SS individuals are at greater risk for developing kidney disease, and also respond differently to antihypertensive therapies compared to salt-resistant (SR) individuals. In this study we used a systems pharmacology model of renal function (presented in a companion article) to evaluate the ability of proposed mechanisms to produce salt-sensitivity. The model reproduced previously published data on renal functional changes in response to salt-intake, and also predicted that glomerular pressure, a variable that is not easily evaluated clinically but is a key factor in renal injury, increases with salt intake in SS hypertension. We then used the model to generate mechanistic insight into the differential blood pressure and glomerular pressure responses to angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, and calcium channel blockers observed in SS and SR hypertension.
Language	English
Publishing date	2017-06
Publishing country	United States
Document type	Journal Article
ZDB-ID	2697010-7
ISSN	2163-8306 ; 2163-8306
ISSN (online)	2163-8306
ISSN	2163-8306
DOI	10.1002/psp4.12177
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Article ; Online: A quantitative systems physiology model of renal function and blood pressure regulation: Model description.

Hallow, K M / Gebremichael, Y

CPT: pharmacometrics & systems pharmacology

2017 Volume 6, Issue 6, Page(s) 383–392

Abstract: Renal function plays a central role in cardiovascular, kidney, and multiple other diseases, and many existing and novel therapies act through renal mechanisms. Even with decades of accumulated knowledge of renal physiology, pathophysiology, and ... ...

Abstract	Renal function plays a central role in cardiovascular, kidney, and multiple other diseases, and many existing and novel therapies act through renal mechanisms. Even with decades of accumulated knowledge of renal physiology, pathophysiology, and pharmacology, the dynamics of renal function remain difficult to understand and predict, often resulting in unexpected or counterintuitive therapy responses. Quantitative systems pharmacology modeling of renal function integrates this accumulated knowledge into a quantitative framework, allowing evaluation of competing hypotheses, identification of knowledge gaps, and generation of new experimentally testable hypotheses. Here we present a model of renal physiology and control mechanisms involved in maintaining sodium and water homeostasis. This model represents the core renal physiological processes involved in many research questions in drug development. The model runs in R and the code is made available. In a companion article, we present a case study using the model to explore mechanisms and pharmacology of salt-sensitive hypertension.
Language	English
Publishing date	2017-06
Publishing country	United States
Document type	Journal Article
ZDB-ID	2697010-7
ISSN	2163-8306 ; 2163-8306
ISSN (online)	2163-8306
ISSN	2163-8306
DOI	10.1002/psp4.12178
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Article ; Online: Model-Based Evaluation of Proximal Sodium Reabsorption Through SGLT2 in Health and Diabetes and the Effect of Inhibition With Canagliflozin.

Brady, Jessica A / Hallow, K Melissa

Journal of clinical pharmacology

2017 Volume 58, Issue 3, Page(s) 377–385

Abstract: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) reduce glucose levels in diabetes by inhibiting renal glucose reabsorption in the proximal tubule (PT), resulting in urinary glucose excretion. A recent large cardiovascular outcomes trial suggested that ...

Abstract	Sodium-glucose cotransporter 2 inhibitors (SGLT2i) reduce glucose levels in diabetes by inhibiting renal glucose reabsorption in the proximal tubule (PT), resulting in urinary glucose excretion. A recent large cardiovascular outcomes trial suggested that the SGLT2i empagliflozin may also decrease risk of renal dysfunction. Because sodium (Na) and glucose reabsorption are coupled through SGLT2, it is hypothesized that the renal benefits may be derived from lowering Na reabsorption in the PT, which would lead to favorable renal hemodynamic changes. However, the quantitative contribution of SGLT2 to PT Na reabsorption, as well as the differences between healthy and diabetic subjects, and the impact of SGLT2i on PT Na reabsorption are unknown. In this study we extended an existing mathematical model of glucose dynamics to account for renal glucose filtration and excretion. We utilized this model to quantify glucose and Na reabsorption through SGLT2 in healthy, controlled, and uncontrolled diabetes and following treatment with canagliflozin. In healthy, controlled diabetic, and uncontrolled diabetic states, Na reabsorption through SGLT2 was found to be 5.7%, 11.5%, and 13.7% of total renal Na reabsorption, and 7.1% to 9.5%, 14.4% to 19.2%, and 17.1% to 22.8% of sodium reabsorption in the PT alone. The model predicted that treatment of controlled diabetes with canagliflozin returns PT Na reabsorption through SGLT2 to normal levels. The degree of increased PT Na reabsorption due to SGLT2 is likely sufficient to drive pathologic changes in renal hemodynamics, and restoration of normal Na reabsorption through SGLT2 may contribute to beneficial renal effects of SGLT2 inhibition.
MeSH term(s)	Canagliflozin/pharmacology ; Diabetes Mellitus, Type 2/blood ; Diabetes Mellitus, Type 2/drug therapy ; Diabetes Mellitus, Type 2/metabolism ; Glucose/metabolism ; Humans ; Hypoglycemic Agents ; Kidney/drug effects ; Kidney/metabolism ; Models, Biological ; Sodium/blood ; Sodium/metabolism ; Sodium-Glucose Transporter 2/blood ; Sodium-Glucose Transporter 2/metabolism ; Sodium-Glucose Transporter 2 Inhibitors/pharmacology
Chemical Substances	Hypoglycemic Agents ; Sodium-Glucose Transporter 2 ; Sodium-Glucose Transporter 2 Inhibitors ; Canagliflozin (0SAC974Z85) ; Sodium (9NEZ333N27) ; Glucose (IY9XDZ35W2)
Language	English
Publishing date	2017-11-16
Publishing country	England
Document type	Journal Article
ZDB-ID	188980-1
ISSN	1552-4604 ; 0091-2700 ; 0021-9754
ISSN (online)	1552-4604
ISSN	0091-2700 ; 0021-9754
DOI	10.1002/jcph.1030
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Article ; Online: Predicted Cardiac Functional Responses to Renal Actions of SGLT2i in the DAPACARD Trial Population: A Mathematical Modeling Analysis.

Yu, Hongtao / Basu, Sanchita / Tang, Weifeng / Penland, Robert C / Greasley, Peter J / Oscarsson, Jan / Boulton, David W / Hallow, K Melissa

Journal of clinical pharmacology

2022 Volume 62, Issue 4, Page(s) 541–554

Abstract: Sodium-glucose cotransporter-2 inhibitors (SGLT2is) have been shown to reduce the risk of worsening heart failure (HF) in subjects with HF and a reduced ejection fraction (HFrEF) in multiple clinical trials. The DAPACARD clinical trial was conducted to ... ...

Abstract	Sodium-glucose cotransporter-2 inhibitors (SGLT2is) have been shown to reduce the risk of worsening heart failure (HF) in subjects with HF and a reduced ejection fraction (HFrEF) in multiple clinical trials. The DAPACARD clinical trial was conducted to examine the effects of dapagliflozin on cardiac substrate uptake, myocardial efficiency, and myocardial contractile work in subjects with type 2 diabetes mellitus. As a complement to the clinical study, a mechanistic mathematical model of cardiorenal physiology was used to quantify the influence of established natriuretic/diuretic effects of SGLT2i on cardiac function (myocardial efficiency and global longitudinal strain). Virtual participants reflecting the participant-level characteristics in the DAPACARD trial were produced by varying model parameters over physiologically plausible ranges. A second virtual population was generated by inducing a state of HFrEF in the DAPACARD virtual participants with type 2 diabetes mellitus for comparison. Cardiac responses to placebo and SGLT2i were simulated over 42 days. Cardiac hemodynamic improvements were predicted in DAPACARD-HFrEF virtual participants but not in DAPACARD virtual participants. In particular, the natriuresis/diuresis induced by SGLT2i improved the global longitudinal strain and myocardial efficiency in DAPACARD-HFrEF virtual participants within the first 14 days (change from baseline: global longitudinal strain, -0.95%; and myocardial efficiency, 0.34%), whereas the global longitudinal strain and myocardial efficiency in DAPACARD virtual participants were slightly worse (change from baseline: global longitudinal strain, 0.35%; and myocardial efficiency: -0.01%). The results of the DAPACARD virtual participants modeling were in line with the clinical data but do not preclude additional effects from other mechanisms of SGLT2i.
MeSH term(s)	Diabetes Mellitus, Type 2/drug therapy ; Heart Failure/drug therapy ; Humans ; Models, Theoretical ; Sodium-Glucose Transporter 2 Inhibitors/pharmacology ; Sodium-Glucose Transporter 2 Inhibitors/therapeutic use ; Stroke Volume
Chemical Substances	Sodium-Glucose Transporter 2 Inhibitors
Language	English
Publishing date	2022-01-05
Publishing country	England
Document type	Clinical Trial ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	188980-1
ISSN	1552-4604 ; 0091-2700 ; 0021-9754
ISSN (online)	1552-4604
ISSN	0091-2700 ; 0021-9754
DOI	10.1002/jcph.1987
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Article ; Online: Predicted Cardiac Hemodynamic Consequences of the Renal Actions of SGLT2i in the DAPA-HF Study Population: A Mathematical Modeling Analysis.

Yu, Hongtao / Tang, Weifeng / Greasley, Peter J / Penland, Robert C / Boulton, David W / Hallow, K Melissa

Journal of clinical pharmacology

2020 Volume 61, Issue 5, Page(s) 636–648

Abstract: The Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) study demonstrated that dapagliflozin, a sodium-glucose cotransporter-2 inhibitor (SGLT2i), reduced heart failure hospitalization and cardiovascular death in patients with ... ...

Abstract	The Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) study demonstrated that dapagliflozin, a sodium-glucose cotransporter-2 inhibitor (SGLT2i), reduced heart failure hospitalization and cardiovascular death in patients with heart failure with reduced ejection fraction (HF-rEF), with and without type 2 diabetes mellitus. Multiple potential mechanisms have been proposed to explain this benefit, which may be multifactorial. This study aimed to quantify the contribution of the known natriuretic/diuretic effects of SGLT2is to changes in cardiac hemodynamics, remodeling, and fluid homeostasis in the setting of HF-rEF. An integrated cardiorenal mathematical model was used to simulate inhibition of SGLT2 and its consequences on cardiac hemodynamics in a virtual population of HF-rEF patients generated by varying model parameters over physiologically plausible ranges and matching to baseline characteristics of individual DAPA-HF trial patients. Cardiovascular responses to placebo and SGLT2i over time were then simulated. The baseline characteristics of the HF-rEF virtual population and DAPA-HF were in good agreement. SGLT2i-induced diuresis and natriuresis that reduced blood volume and interstitial fluid volume, relative to placebo within 14 days. This resulted in decreased left ventricular end-diastolic volume and pressure, indicating reduced cardiac preload. Thereafter, blood volume and interstitial fluid volume again began to accumulate, but pressures and volumes remained shifted lower relative to placebo. After 1 year, left ventricle mass was lower and ejection fraction was higher than placebo. These simulations considered only hemodynamic consequences of the natriuretic/diuretic effects of SGLT2i, as other mechanisms may contribute additional benefits besides those predictions.
MeSH term(s)	Benzhydryl Compounds/pharmacology ; Benzhydryl Compounds/therapeutic use ; Blood Glucose ; Blood Volume/drug effects ; Computer Simulation ; Diabetes Mellitus, Type 2/drug therapy ; Diuresis/drug effects ; Glomerular Filtration Barrier ; Glucosides/pharmacology ; Glucosides/therapeutic use ; Heart Failure/drug therapy ; Hematocrit ; Hemodynamics/drug effects ; Humans ; Models, Theoretical ; Natriuresis/drug effects ; Sodium-Glucose Transporter 2 Inhibitors/pharmacology ; Sodium-Glucose Transporter 2 Inhibitors/therapeutic use
Chemical Substances	Benzhydryl Compounds ; Blood Glucose ; Glucosides ; Sodium-Glucose Transporter 2 Inhibitors ; dapagliflozin (1ULL0QJ8UC)
Language	English
Publishing date	2020-10-22
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	188980-1
ISSN	1552-4604 ; 0091-2700 ; 0021-9754
ISSN (online)	1552-4604
ISSN	0091-2700 ; 0021-9754
DOI	10.1002/jcph.1769
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