Influence of serum chloride concentrations on the renin-angiotensin-aldosterone system in dogs with congestive heart...

Chloride is a key determinant of macula densa signaling and renin release, but its relationship with systemic renin-angiotensin-aldosterone system (RAAS) activity in naturally occurring heart failure is incompletely defined. We evaluated associations between serum chloride concentration and circulating RAAS metabolites in 147 dogs [20 healthy, 39 preclinical heart disease, and 88 congestive heart failure (CHF)]. Circulating angiotensin metabolites, aldosterone, and angiotensin-converting enzyme (ACE) and ACE2 activity were quantified by liquid chromatography-mass spectrometry. Associations between serum chloride and RAAS components were assessed using HC3 robust multivariable linear regression adjusted for sex, ACE inhibitor use, and serum bicarbonate. Dogs with CHF had higher circulating RAAS metabolites than healthy and preclinical dogs. Serum chloride was inversely correlated with multiple RAAS metabolites, including Ang I (r_s = -0.515) and Ang 1-7 (r_s = -0.546; both P < 0.0001). Lower serum chloride was independently associated with higher concentrations of angiotensin peptides (Ang I, II, III, IV, and Ang 1-7) and aldosterone, with each 5 mmol/L decrease corresponding to 32%-45% increases in angiotensin metabolites and a 39% increase in aldosterone (all adjusted P ≤ 0.02). Hypochloremia (<100 mEq/L) identified a distinct RAAS phenotype characterized by higher downstream angiotensin metabolites, including Ang II, III, and IV (all adjusted P ≤ 0.03). Chloride was not associated with ACE or ACE2 activity. Serum chloride is independently associated with systemic RAAS activation in dogs with heart disease, supporting an association between lower serum chloride concentrations and enhanced upstream of RAAS pathway flux.NEW & NOTEWORTHY This study demonstrates that lower serum chloride is independently associated with greater systemic RAAS activation in dogs with naturally occurring heart disease. Hypochloremia identified a distinct RAAS phenotype characterized by increased downstream angiotensin metabolites despite no differences in ACE or ACE2 activity. Because dogs develop heart failure with clinical and neurohormonal features similar to humans, these findings provide translational evidence linking lower serum chloride concentrations with enhanced upstream RAAS pathway activity in cardiovascular disease.