@article{10.37349/emed.2026.1001432,
abstract = {Patients with acute heart failure show substantial variation in natriuretic and decongestive responses to loop diuretics, yet the physiological basis of this heterogeneity remains incompletely understood. Chloride status has emerged as a candidate marker of cardiorenal response, supported by associations with neurohormonal activation, diuretic efficiency and residual congestion, together with chloride-sensitive WNK signalling. Separately, the apelinergic system exerts acute renal and haemodynamic effects in humans, while experimental studies indicate that apelin-receptor signalling depends on mechanical and molecular context. No study, however, has directly tested whether chloride state modifies apelin responsiveness, and acute sodium depletion or angiotensin II exposure did not attenuate apelin responses in controlled human studies. This Perspective proposes that chloride state may modify apelin responsiveness when chloride-conditioned renal physiology coexists with persistent myocardial loading. Chloride is therefore treated as a continuous, longitudinal state variable rather than a therapeutic target or surrogate for receptor function. We also define the competing biomarker and causal interpretations, propose research measurements and plausible sensitivity thresholds, and outline a staged translational testing framework. Support would require incremental information beyond sodium and established risk measures, a reproducible mechanistic interaction, and state-dependent variation in directly measured agonist response. Confirmation could inform physiological enrichment of future apelin-agonist trials, whereas failure could retain chloride as a marker of decongestive physiology rather than an apelin-modifying mechanism.},
author = {Alfonso, Dominic Marcel},
doi = {10.37349/emed.2026.1001432},
journal = {Exploration of Medicine},
elocation-id = {1001432},
title = {Does chloride state modify apelin responsiveness in heart failure?},
url = {https://www.explorationpub.com/Journals/em/Article/1001432},
volume = {7},
year = {2026}
}