Mechanism and Effects of Manipulating Chloride Homeostasis in Stable Heart Failure

The overarching goal of this study is to develop a comprehensive understanding of the biology and therapeutic potential of sodium-free chloride supplementation. While sodium homeostasis has been the focus of substantial investigation, very little research has been devoted to understanding chloride homeostasis. Thus, this proposal is designed to obtain the full spectrum of information pertaining to chloride, such as novel areas with great interest by the scientific community (i.e. modulation of the WNK-kinase system and the use of exosomes), to more practical/basic questions (i.e. what happens to sodium chloride balance when a patient is challenged with chloride).

This study is designed as a highly controlled inpatient "GCRC" arm to be compared to a real world efficacy study that has been proposed as a separate study. With extensive biobanking and analysis of samples in the inpatient setting, we will be able to deliver a great wealth of information on the biology and therapeutic potential of manipulating chloride homeostasis in heart failure.

Inclusion criteria

• Meticulous history of medical compliance and attendance of appointments
• Stable heart failure as defined by:

• Absence of hospitalizations for 90 days
• Stable diuretic and medical therapy for 30 days
• Opinion of the patient's treating physician (Heart Failure Cardiologist) that the patient is at optimal volume status
• Evidence based heart failure treatment with maximally-tolerated doses of a beta blocker, ACE/ARB/neprilysin inhibitor and aldosterone antagonist
• Chronic loop diuretic therapy with ≥ 40 mg of furosemide equivalents
• Serum chloride <102 mmol/L

Exclusion criteria

• Inability to commit to or comply with the rigorous study protocol
• Use of a thiazide diuretic in the last 30 days
• History of metabolic or respiratory acidosis
• Use of metformin, acetazolamide, or any other agent that could predispose to acidosis. Patients who are on metformin may be enrolled if their metformin can be safely discontinued for the randomized periods in each arm. Any participants who have consistently elevated Blood glucose readings > 200 mg/dL while inpatient will not be enrolled.
• Serum bicarbonate level <24mmol/L
• Serum pH <7.3
• Estimated glomerular filtration rate <30 mL/min or prior or current history of renal replacement therapy
• Anemia, as defined by Hemoglobin <8.0 g/dL at screening visit
• Urinary incontinence or significant bladder dysfunction (post-void residual at screening >300 mL)
• Use of chloride containing medications that provide more than 5 mmol/day of chloride if the medication cannot be discontinued or substituted
• Appears unlikely, or unable to participate in the required study procedures, as assessed by the study PI or research RN (ex: clinically-significant psychiatric, addictive, or neurological disease)
• Inability to give written informed consent or follow study protocol