The 'Chloride Theory' for Heart Failure Pathophysiology: An Updated Narrative Review 2025.

Area of Science:

• Cardiology
• Nephrology
• Internal Medicine

Background:

• Traditional heart failure (HF) research emphasizes sodium and water balance.
• The chloride theory, proposed in 2017, links serum chloride to plasma volume, hemodynamics, and neurohormonal activity in HF.
• Emerging clinical evidence necessitates an update on the chloride theory's role in HF management.

Purpose of the Study:

• To provide an updated perspective on the chloride theory in heart failure.
• To examine diuretic classification, guideline-directed medical therapy, and loop diuretic resistance through a chloride-centered lens.
• To summarize the prognostic significance of serum chloride in acute HF and differentiate sodium's and chloride's pathophysiologic roles.

Main Methods:

• This study is a narrative review of existing clinical evidence.
• It synthesizes data on serum chloride concentration, HF progression, and treatment responses.
• The review analyzes diuretic mechanisms, therapeutic advancements, and prognostic markers related to chloride.

Main Results:

• Serum chloride concentration is integral to understanding fluid shifts, hemodynamics, and neurohormonal responses in HF.
• A chloride-centered approach offers new insights into diuretic efficacy and resistance.
• Changes in serum chloride during acute HF carry prognostic relevance.

Conclusions:

• The chloride theory provides a unifying framework for understanding HF pathophysiology and treatment.
• Integrating chloride dynamics into HF management and monitoring may optimize therapeutic strategies.
• Further research into the distinct roles of sodium and chloride in HF is warranted.