Neurohormonal Activation and Renal Chloride Avidity in Acute Heart Failure: Clinical Evidence Supporting the "Chloride Theory".

ABSTRACT

INTRODUCTION: Heart failure (HF) progression according to changes in the serum chloride concentration ([sCl-]) was recently proposed as the "chloride (Cl) theory" for HF pathophysiology. The present study examined the association of neurohormones and renal Cl avidity to determine their contribution to acute HF and their involvement to the "Cl theory." METHODS: Data from 29 patients with acute HF (48% men; 80.3 ± 12 years) were analyzed. Blood and urine samples were obtained before decongestive therapy. Clinical tests included peripheral blood, serum and spot urinary electrolytes, b-type natriuretic peptide (BNP), and plasma neurohormones. RESULTS: In the 29 patients, urinary Cl concentrations ([uCl-]) inversely correlated with log (plasma renin activity [PRA]) (r = -0.64, p = 0.0002) and log (plasma aldosterone concentration) (r = -0.50, p = 0.006). The [sCl-]‒[uCl-] difference positively correlated with log PRA (r = 0.63, p = 0.0002) and log (plasma aldosterone concentration) (r = 0.49, p = 0.008). Patients were divided into 2 groups according to the [sCl-]‒[uCl-] difference, an excretion (low renal Cl avidity) group and an absorption (high renal Cl avidity) group. Compared with the excretion group (-77 to ‒5 mEq/L; n = 14), the absorption group (1-84 mEq/L; n = 15) exhibited greater renal impairment (serum creatinine; 1.45 ± 0.63 vs. 1.00 ± 0.38 mg/d, p = 0.029) and cardiac burden (log BNP; 2.99 ± 0.3 vs. 2.66 ± 0.32 pg/mL, p = 0.008), higher log PRA (0.20 ± 0.58 vs. -0.25 ± 0.35 ng/mL/h, p = 0.018), and lower fractional urinary Cl excretion (1.34 ± 1.3 vs. 5.33 ± 4.1%, p < 0.001). CONCLUSION: Renal Cl avidity differs in acute HF, i.e., excretion (low renal Cl avidity) versus absorption (high renal Cl avidity) types, involving renin-aldosterone-angiotensin activity as the underlying mechanism, which provides the neurohormonal background for the "Cl theory." A version of this study was presented in part at the annual international scientific assembly (ACC.23) of the American College of Cardiology, March 4-6, 2023.