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Clinical Trial 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.


Clinical Trial 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. ;


Study Design


Related Conditions & MeSH terms


NCT number NCT03837470
Study type Interventional
Source University of Utah
Contact
Status Completed
Phase Early Phase 1
Start date May 6, 2019
Completion date February 20, 2020

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