Evaluation of Renal Sodium Excretion After Salt Loading in Heart Failure With Preserved Ejection Fraction
| Status: | Not yet recruiting |
|---|---|
| Conditions: | Cardiology |
| Therapuetic Areas: | Cardiology / Vascular Diseases |
| Healthy: | No |
| Age Range: | 21 - 80 |
| Updated: | 2/14/2019 |
| Start Date: | April 2019 |
| End Date: | April 2020 |
| Contact: | Habeeb Mohammad |
| Email: | habeeb.mohammad@hsc.utah.edu |
| Phone: | 801-581-8573 |
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.
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.
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.
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.
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
We found this trial at
1
site
201 Presidents Circle
Salt Lake City, Utah 84108
Salt Lake City, Utah 84108
801) 581-7200
Principal Investigator: Adhish Agarwal, MD
Phone: 801-581-8573
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