Evaluation of Renal Sodium Excretion After Salt Loading in Heart Failure With Preserved Ejection Fraction
Condition: Heart Failure With Preserved Ejection Fraction
MeSH terms: Heart Failure
Study type: Interventional
Phase: Early Phase 1

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.
    

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.
    

Intervention name(s): 0.9% Sodium Chloride; Furosemide 40 mg
Intervention type(s): Drug; Drug
Intervention description(s): Intravenous infusion of 0.25ml/kg/min of 0.9% sodium chloride intravenously for a total of 60 minutes; Bolus intravenous injection of 40 mg furosemide
Other intervention name(s): normal saline
Intervention MeSH terms: Furosemide
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Basic Science