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Evaluation of Renal Sodium Excretion After Salt Loading in Heart Failure With Preserved Ejection Fraction (ERES-HFpEF)

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ClinicalTrials.gov Identifier: NCT03837470
Recruitment Status : Recruiting
First Posted : February 12, 2019
Last Update Posted : May 30, 2019
Sponsor:
Collaborator:
University of Utah Center for Clinical and Translational Science
Information provided by (Responsible Party):
Adhish Agarwal, University of Utah

Brief Summary:
Heart failure (HF) affects 2-3% of the population, and is characterized by impaired sodium balance which results in fluid overload. Ejection fraction, a measure of systolic function, is reduced in only about half of all HF patients. Incidence of heart failure with preserved ejection fraction (HFpEF) has increased in the last 20 years making it a growing public health problem. Currently, most patients admitted to the hospital with heart failure have preserved rather than reduced ejection fractions. However, to date it remains unknown why patients with HFpEF retain salt and water. The hypothesis is that patients with clinical HFpEF have an impaired renal response to salt loading, intravascular expansion and diuretics. Characterization of the salt and water excretory renal response to intravascular salt, fluid and diuretic load in patients with HFpEF will provide insight into the pathophysiology of HFpEF, and may help in the development of novel strategies to target renal sodium handling in patients with HFpEF. This characterization is the primary objective of this pilot project.

Condition or disease Intervention/treatment Phase
Heart Failure With Preserved Ejection Fraction Drug: 0.9% Sodium Chloride Drug: Furosemide 40 mg Early Phase 1

Detailed Description:

In patients with heart failure with reduced ejection fraction (HFrEF), poor renal perfusion and neuro-hormonal activation cause renal salt and water retention. In contrast to HFrEF, patients with HFpEF have blunted neuro-hormonal activation, and other mechanisms likely cause fluid overload. Investigators have proposed several mechanisms including inflammatory state, endothelial dysfunction, decreased vascular compliance, pulmonary hypertension, and reduced nitric oxide (NO) bioavailability. However, the etiology and pathophysiology of fluid overload in HFpEF patients remains controversial.

Renal dysfunction is common in patients with HFpEF, and is associated with cardiac remodeling. HFpEF is associated with coronary microvascular endothelial activation and oxidative stress, which through reduction of NO dependent signaling contributes to the high cardiomyocyte stiffness and hypertrophy. Plasma sodium stiffens vascular endothelium and reduces NO release. Thus, renal sodium retention may play a pivotal role in the pathophysiology of HFpEF. Patients with HFrEF indeed have abnormal renal sodium excretion in response to salt load; however, it remains unclear if patients with HFpEF also have an impaired renal sodium excretion in response to a salt load, volume expansion or diuretics.

Since (as noted above) renal sodium retention may play an important role in the pathophysiology of HFpEF, it may be critically important to characterize renal sodium handling in patients with clinical HFpEF in response to salt loading, intravascular expansion and diuretic challenge. Impaired sodium excretion has been previously demonstrated in response to volume expansion in pre-clinical systolic and diastolic dysfunction, but not in patients with clinical HFpEF. Further, it is of note that this impairment in renal sodium excretion is rescued by exogenous B-type natriuretic peptide (BNP), which is a natriuretic peptide that is increased in most patients with HFpEF. It is possible, although not reported, that baseline BNP [which is commonly assessed by N-terminal prohormone of BNP (NT-proBNP)] levels affect renal sodium handling in HFpEF patients in response to salt and volume load, or diuretic challenge. It is also unknown if baseline kidney function, measured by estimated glomerular filtration rate (eGFR), affects natriuresis in patients with HFpEF after salt loading or diuretic challenge. Renal tubular function may also have important effects on salt retention in HF patients.

Characterization of the natriuretic response to intravascular salt and volume load and diuretic challenge, and of tubular function, in patients with HFpEF will provide insight into the pathophysiology of HFpEF, and may help in the development of novel strategies to target renal sodium handling in patients with HFpEF.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 15 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: Evaluation of Renal Sodium Excretion After Salt Loading in Heart Failure With Preserved Ejection Fraction
Actual Study Start Date : May 6, 2019
Estimated Primary Completion Date : April 2020
Estimated Study Completion Date : April 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Saline Loading and Diuretic Challenge
Subjects receive intravenous infusion of 0.9% Sodium Chloride, followed by diuretic challenge with bolus injection of Furosemide 40 mg
Drug: 0.9% Sodium Chloride
Intravenous infusion of 0.25ml/kg/min of 0.9% sodium chloride intravenously for a total of 60 minutes
Other Name: normal saline

Drug: Furosemide 40 mg
Bolus intravenous injection of 40 mg furosemide




Primary Outcome Measures :
  1. Urinary Sodium Excretion [ Time Frame: 5 Hours ]
    Amount of sodium excretion following saline loading and diuretic challenge will be compared between HFpEF patients and controls

  2. Urine Volume [ Time Frame: 5 Hours ]
    Volume of urine collected following saline loading and diuretic challenge will be compared between HFpEF patients and controls


Secondary Outcome Measures :
  1. Change in NT-proBNP [ Time Frame: 5 Hours ]
    Average change in NT-proBNP values before and after saline loading and diuretic challenge will be compared between HFpEF patients and controls

  2. Serum Aldosterone [ Time Frame: 5 Hours ]
    Serum Aldosterone levels at baseline, after saline loading and after furosemide administration compared between HFpEF patients and controls

  3. Plasma Renin Activity [ Time Frame: 5 Hours ]
    Plasma renin activity levels at baseline, after saline loading and after furosemide administration compared between HFpEF patients and controls

  4. Plasma Nor-epinephrine [ Time Frame: 5 Hours ]
    Plasma nor-epinephrine levels at baseline, after saline loading and after furosemide administration compared between HFpEF patients and controls


Other Outcome Measures:
  1. Urinary Exosomes [ Time Frame: 5 Hours ]
    Sodium transporters in Urinary exosomes will be characterized and compared between HFpEF patients and controls



Information from the National Library of Medicine

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Ages Eligible for Study:   21 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • History of chronic (> 6 months) heart failure with current New York Heart Association II-III symptoms
  • Left ventricular ejection fraction > 50% on a clinically indicated echocardiogram obtained within last 12 months
  • Clinical compensated heart failure
  • On constant medical therapy for heart failure; without changes in heart failure medication regimen (including diuretics) for previous 14 days and not expected to change in the next 2 days

Exclusion Criteria:

  • Unable to comply with protocol or procedures
  • Uncontrolled severe hypertension: systolic blood pressure > 160 mmHg
  • Significant renal impairment as defined by estimated glomerular filtration rate < 30ml/min/1.73m^2 determined by Chronic Kidney Disease - Epidemiology Collaboration equation
  • Significant proteinuria (> 0.5 g protein/daily protein or equivalent)
  • Body Mass Index > 40 kg/m^2
  • Acute coronary syndrome within last 4 weeks
  • Coronary revascularization procedures (percutaneous coronary intervention or cardiac artery bypass graft) or valve surgery within 30 days of screening
  • Cardiac resynchronization therapy, with or without implantable cardioverter defibrillator within 90 days of screening
  • Clinically relevant cardiac valvular disease
  • Hypertrophic or restrictive cardiomyopathy, constrictive pericarditis, active myocarditis, active endocarditis, or complex congenital heart disease
  • Cirrhosis of the liver
  • History of known hydronephrosis
  • History of adrenal insufficiency

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03837470


Contacts
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Contact: Habeeb Mohammad 801-581-8573 habeeb.mohammad@hsc.utah.edu
Contact: Adhish Agarwal, MD 801-581-6709 adhish.agarwal@hsc.utah.edu

Locations
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United States, Utah
University of Utah Recruiting
Salt Lake City, Utah, United States, 84132
Contact: Habeeb Mohammad    801-581-8573    habeeb.mohammad@hsc.utah.edu.edu   
Contact: Adhish Agarwal, MD    801-581-6709    adhish.agarwal@hsc.utah.edu   
Principal Investigator: Adhish Agarwal, MD         
Sponsors and Collaborators
Adhish Agarwal
University of Utah Center for Clinical and Translational Science
Investigators
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Principal Investigator: Adhish Agarwal, MD University of Utah

Publications:

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Responsible Party: Adhish Agarwal, Associate Professor, Nephrology, University of Utah
ClinicalTrials.gov Identifier: NCT03837470     History of Changes
Other Study ID Numbers: IRB_00112270
First Posted: February 12, 2019    Key Record Dates
Last Update Posted: May 30, 2019
Last Verified: May 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Heart Failure
Heart Diseases
Cardiovascular Diseases
Furosemide
Diuretics
Natriuretic Agents
Physiological Effects of Drugs
Sodium Potassium Chloride Symporter Inhibitors
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action