Chloride in Heart Failure Syndrome: Its Pathophysiologic Role and Therapeutic Implication

Abstract

Until recently, most studies of heart failure (HF) focused on body fluid dynamics through control of the sodium and water balance in the body. Chloride has remained largely ignored in the medical literature, and in clinical practice, chloride is generally considered as an afterthought to the better-known electrolytes of sodium and potassium. In recent years, however, the important role of chloride in the distribution of body fluid has emerged in the field of HF pathophysiology. Investigation of HF pathophysiology according to the dynamics of serum chloride is rational considering that chloride is an established key electrolyte for tubulo-glomerular feedback in the kidney and a possible regulatory electrolyte for body fluid distribution. The present review provides a historical overview of HF pathophysiology, followed by descriptions of the recent attention to the electrolyte chloride in the cardiovascular field, the known role of chloride in the human body, and recent new findings regarding the role of chloride leading to the proposed 'chloride theory' hypothesis in HF pathophysiology. Next, vascular and organ congestion in HF is discussed, and finally, a new classification and potential therapeutic strategy are proposed according to the 'chloride theory'.

Mechanistic insights into chloride‐related heart failure progression according to the plasma volume status

“…A decrease in the serum chloride concentration would further promote the vicious cycle of enhanced activity of RAAS by further lowering of the urinary chloride supply to the macula densa cells in the kidney 13,14 . This sophisticated concept of the relationship between hypochloraemia and RAAS activity is conceivable and consistent with the ‘chloride theory’ for HF pathophysiology 3,15,16 . Although this study is observational and does not allow for causal inference, a change in the serum chloride concentration could be considered a representative adaptative mechanism of the dysfunctional heart to help unload its cardiac burden via modulating the plasma volume status by recruiting the tonicity potential of chloride to regulate the water distribution across body fluid compartments as following underlying mechanism.…”

“…13,14 This sophisticated concept of the relationship between hypochloraemia and RAAS activity is conceivable and consistent with the 'chloride theory' for HF pathophysiology. 3,15,16 Although this study is observational and does not allow for causal inference, a change in the serum chloride concentration could be considered a representative adaptative mechanism of the dysfunctional heart to help unload its cardiac burden via modulating the plasma volume status by recruiting the tonicity potential of chloride to regulate the water distribution across body fluid compartments as following underlying mechanism. Chloride is thought to have tonicity potential and regulates water distribution across body compartments in the human body.…”

“…Chloride is thought to have tonicity potential and regulates water distribution across body compartments in the human body. 15,16 By this mechanism, body fluid in the vascular space (compartment) is thought to extravasate into the interstitial space (compartment) and induce a decrease in the effective blood volume in patients with worsening HF and a decreased serum chloride concentration, among whom many HF patients would present with auscultatory bilateral basal pulmonary rales (Table 2).…”

“…19 The 'chloride theory' for HF pathophysiology 3,6 does not fully explain the complex HF pathophysiology, but in clinical practice at present, this theory could provide a primary care and management system for diuretic treatment of HF patients, with attention to the serum chloride concentration and changes central to this system. 15,16 Anyway, additional studies are required to clarify the role of chloride in haemodynamic contribution to the HF pathophysiology, 15,16 such as evaluation of the concentrations of chloride in the different types of HF (e.g. HF with preserved vs. reduced ejection fraction) with different total cardiac burden and different cardiac functional reserve.…”

Cardiorenal syndrome: Decongestion in heart failure across wide spectrum of kidney pathophysiology

“…Dyschloremia is postulated as one of the main causes of worsening HF during decongestive treatment. 59 A new classification of diuretics based on their effect on serum chloride concentration has been proposed in recent years. This concept is consistent with recent clinical observations that chloride-regaining diuretics preserve plasma volume, enhance vascular "tonicity" and avoid diuretic resistance (Table 2).…”