Chloride in Heart Failure: The Neglected Electrolyte

Arietje J.L. Zandijk, BSC; Margje R. van Norel, BSC; Florine E.C. Julius, BSC; Nariman Sepehrvand, MD, PHD; Neesh Pannu, MD, SM; Finlay A. McAlister, MD, MSC; Adriaan A. Voors, MD; Justin A. Ezekowitz, MBBCH, MSC

Disclosures

JACC Heart Fail. 2022;9(12):904-915. 

In This Article

The Effect of HF Therapy on Chloride Level

Salt Restriction

Serum electrolyte concentrations may be influenced by the amount of dietary sodium chloride (the most abundant dietary salt) intake.[33] Despite limited evidence for the beneficial effect of sodium or fluid restriction in HF, the current HF guidelines endorse that strategy to minimize the risk of volume overload and for symptom improvement. However, recently attention has focused on potential detrimental effects from salt restriction, possibly caused by further neurohormonal activation and HF progression, which are caused by hypochloremia,[20] hyponatremia, or both. The relationship between a low intake and low serum electrolyte concentrations remains unknown for patients with HF. Moreover the actual clinical impact of salt restriction is yet to be established in this patient population. This question is expected to be answered by the ongoing SODIUM-HF (Study of Dietary Intervention Under 100 MMOL in Heart Failure; NCT02012179) trial.

HF Medications

Although there is no compelling evidence that diuretic agents improve survival in patients with HF, they are the first-line therapy to prevent and treat fluid overload and to improve symptoms, through renal sodium and chloride wasting. Diuretics may have differences in tubuloglomerular feedback response, with loop diuretic agents disrupting it whereas others do not. This phenomenon has implications for sodium and chloride handling and neurohormonal response. Inhibition of the Na-K-2Cl cotransporter results in less electrolyte reabsorption, which will lead to extravascular volume depletion and consequently neurohormonal activation. The latter leads to free water reabsorption and worsening of hypochloremia. Loop diuretic agents can increase chloride excretion by ~20-fold. Compared with sodium and potassium excretion, there is an extra 10% to 20% chloride loss with loop diuretic agents.[20] As the affected pump (ie, Na-K-2Cl) is located in the thick ascending limb of the loop of Henle, further along the nephron there is still a possibility to reabsorb sodium, which prevents hyponatremia in diuretic therapy. More distally, there is minimal possibility to reabsorb chloride, hence we observe hypochloremia. Thiazides can cause both hyponatremia and hypochloremia through inhibiting the Na-Cl cotransporter in the distal convoluted tubule.[10] Diuretic treatment in combination with salt restriction may limit tubular delivery and reabsorption of chloride even more and aggravate the hypochloremia.[25] Not surprisingly, a higher diuretic use is reported among patients with the lowest quartile of serum chloride level.[30]

Treatment with mineralocorticoid receptor antagonists may not ameliorate hypochloremia, but it can prevent further decline in serum chloride levels in patients with HF. Studies have shown no association between spironolactone and a decrease in serum chloride concentrations.[19] The carbonic anhydrase inhibitor, acetazolamide, increases serum chloride levels and decreases HCO3 independently of sodium, through inhibition of the intracellular and luminal carbonic anhydrase in the proximal tubule.[3]

No studies have explored the effect of treatment with angiotensin receptor blockers, angiotensin converting enzyme inhibitors, or beta-blockers on chloride homeostasis. Hyperkalemia is the only electrolyte disturbance that is widely reported with angiotensin receptor blocker and angiotensin converting enzyme inhibitor therapies.

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