Mechanism and Effects of Manipulating Chloride Homeostasis in Acute Heart Failure

The overarching goal of this proposal 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). The proposed outpatient study has been designed
to serve as a real world efficacy study. With extensive biobanking and analysis of samples in
the proposed setting, there is the potential to be able to deliver a great wealth of
information on the biology and therapeutic potential of manipulating chloride homeostasis in
heart failure.

Research confirms that many heart failure therapies demonstrate measurable benefit in highly
controlled environments, but lack effectiveness when studied in decompensated patients
receiving standard decongestive therapies. As such, this study seeks to understand the
effects of chloride supplementation on volume-overloaded patients concomitantly treated with
IV diuretics.

Inclusion Criteria:

- Clinical diagnosis of decompensated heart failure with at least one objective sign of
volume overload (rales, edema, elevated jugular venous pressure (JVP), or weight gain
of at least 5 pounds)

- A projected need by the treating clinician for protocol-driven treatment with IV
diuretics for at least 3 days

- Chronic loop diuretic use

Exclusion Criteria:

- Inability to commit to or comply with serial visits for treatment in the Yale
Transitional Care Center (YTCC)

- History of severe metabolic or respiratory acidosis

- Use of metformin, acetazolamide, or any other agent that could predispose to acidosis

- Serum bicarbonate level <20mmol/L

- Estimated glomerular filtration rate <20 mL/min or renal replacement therapy

- Appears unlikely, or unable to participate in the required study procedures, as
assessed by the study PI or research registered nurse (RN) (ex: clinically-significant
psychiatric, addictive, or neurological disease)

- Inability to give written informed consent or follow study protocol