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

Figures

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  Fig. 1. Three principal pathways underlying the chloride theory for acute heart failure pathophysiology, with supporting clinical evidence: (1) vascular volume (blue arrow); (2) cardiac output (red arrow); and (3) renin–angiotensin–aldosterone system (green arrow). AVP arginine vasopressin, Cl chloride, RAAS renin–angiotensin–aldosterone system

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  Fig. 2. Updated chloride theory to explain fluid dynamics during the course of worsening heart failure. Solid lines indicate enhanced supply or stimulatory effects, whereas dotted lines indicate reduced supply or inhibitory effects.The large green square represents the kidney as the primary site of electrolyte and water reabsorption. AVP arginine vasopressin, Cl chloride, Na sodium, RAAS renin–angiotensin–aldosterone system. Adapted from original 2021 publication with modification [reference 14]

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  Fig. 3. Heart failure (HF) treatment and resolution of worsening HF based on the chloride theory; A conventional (Loop/thiazide) diuretic therapy, B carbonic anhydrase inhibitor/SGLT2 inhibitor, C V2-receptor antagonist, and D chloride supplementation. Blue and yellow blocks represent the inhibition of the chloride/sodium and water absorption. Red block indicates enhanced chloride reabsorption and bicarbonate excretion. Solid lines represent enhanced supply or stimulatory effects, and dotted lines represent reduced supply or inhibitory effects. Large green square represents the kidney as the primary site of electrolyte and water reabsorption. AVP arginine vasopressin, Cl chloride, HCO3 bicarbonate, Na sodium, SGLT2 sodium-glucose co-transporter-2. Adapted from original 2021 publication with modification [reference 14]

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  Fig. 4. Proposed cardio-pulmonary interactions mediated by renal acid/base homeostasis, involving reciprocal changes in chloride and bicarbonate that may influence carbon dioxide handling. Solid lines indicate enhanced or stimulatory effects, whereas dotted lines indicate reduced or inhibitory effects. The blue-shaded region highlights components of the chloride theory in HF pathophysiology. RAA renin–angiotensin–aldosterone