Evaluation of Renal Sodium Excretion After Salt Loading in Heart Failure With Preserved Ejection Fraction

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Evaluation of Renal Sodium Excretion After Salt Loading in Heart Failure With Preserved Ejection Fraction

Conditions
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Heart Failure With Preserved Ejection Fraction

Intervention / Treatment
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* Drug: 0.9% Sodium Chloride
* Drug: Furosemide 40 mg


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Saline Loading and Diuretic Challenge<br>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<br>* Intravenous infusion of 0.25ml/kg/min of 0.9% sodium chloride intravenously for a total of 60 minutes<br>* Other names: normal saline;Drug: Furosemide 40 mg<br>* Bolus intravenous injection of 40 mg furosemide<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Urinary Sodium Excretion | Amount of sodium excretion following saline loading and diuretic challenge will be compared between HFpEF patients and controls | 5 Hours | 
| Urine Volume | Volume of urine collected following saline loading and diuretic challenge will be compared between HFpEF patients and controls | 5 Hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in NT-proBNP | Average change in NT-proBNP values before and after saline loading and diuretic challenge will be compared between HFpEF patients and controls | 5 Hours | 
| Serum Aldosterone | Serum Aldosterone levels at baseline, after saline loading and after furosemide administration compared between HFpEF patients and controls | 5 Hours | 
| Plasma Renin Activity | Plasma renin activity levels at baseline, after saline loading and after furosemide administration compared between HFpEF patients and controls | 5 Hours | 
| Plasma Nor-epinephrine | Plasma nor-epinephrine levels at baseline, after saline loading and after furosemide administration compared between HFpEF patients and controls | 5 Hours |