The chloride paradigm shift in heart failure: From neglected ion to keystone of precision diuretic therapy

Chloride, together with sodium, is one of the major extracellular ions and plays a critical yet often overlooked role in the pathophysiology of heart failure (HF). Beyond its passive role in maintaining electroneutrality and osmotic balance, chloride actively contributes to renal tubular transport via Na⁺-Cl^- cotransporter (NCC) and Na⁺-K⁺-2Cl^- cotransporter (NKCC), regulates acid-base homeostasis through bicarbonate exchange, and modulates neurohormonal activity by influencing renin release at the macula densa. In HF, hypochloraemia (whether dilutional or due to true ionic depletion) activates maladaptive mechanisms including enhanced sodium reabsorption, metabolic alkalosis, and sustained activation of the renin-angiotensin-aldosterone system. These alterations collectively exacerbate fluid retention, promote diuretic resistance, and worsen congestion. Emerging evidence suggests that low serum chloride levels are independently associated with higher mortality, reduced natriuretic response, and poorer decongestion outcomes. This review synthesizes the pathophysiological and clinical significance of chloride in HF and examines emerging therapeutic strategies aimed at restoring chloride homeostasis and improving diuretic response. These include sodium-free chloride formulations, chloride-sparing diuretics, and hypertonic saline solutions, with trials such as SMAC-HF and SALT-HF suggesting clinical benefit, particularly in hypochloraemic patients. Novel technologies, such as automated chloride-balanced diuresis systems, represent a promising tool for individualized fluid management. Recognizing hypochloraemia as a modifiable therapeutic target (rather than a bystander) may lead to a paradigm shift in the approach to congestion and volume overload in HF. A chloride-guided strategy offers the potential for more effective and personalized decongestive therapy.