The ‘Chloride Theory’ for Heart Failure Pathophysiology: An Updated Narrative Review 2025

Most studies of heart failure (HF) syndromes have focused on fluid regulation, particularly the balance of sodium and water. Approximately 10 years ago, in 2017, the "chloride theory" was proposed as a unifying hypothesis, suggesting that changes in serum chloride concentration are associated with shifts in plasma volume, hemodynamics, and neurohormonal activity during HF progression and treatment. This narrative review updates the chloride theory based on emerging clinical evidence. It further examines diuretic classification from a chloride-centered perspective, recent advances in guideline-directed medical therapy, and the potential role of chloride in loop diuretic resistance and its management. In addition, the review summarizes the prognostic relevance of changes in serum chloride during acute HF and the distinct pathophysiologic roles of sodium and chloride. Overall, this review provides an integrated perspective on HF pathophysiology, therapeutic strategies, and clinical monitoring within a chloride-centered framework.