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Decongestion: more than meets the eye!

This article refers to ‘Contrasting acute and chronic effects of tolvaptan on serum osmolality in the EVEREST trial’†, by M. Vaduganathan et al., published in this issue on page 183–189. Being the most abundant molecule on earth, water is vital for all known forms of life. Water homeostasis in the human body is meticulously regulated, with plasma osmolality residing in a tight range at 285–295 mOsm/L under normal circumstances. This is important as even minute variations in plasma osmolality place the cellular compartment under stress: hypotonicity causes cell swelling; cell shrinking is observed in the case of hypertonicity. Arginine vasopressin (AVP), or antidiuretic hormone, is therefore released from a threshold of ∼280 mOsm/L, with levels rising steeply when plasma osmolality increases (Figure 1).1 Through V2 receptor stimulation, AVP promotes both the synthesis and availability of aquaporin-2 channels in the collecting ducts of the nephron, which is the major driver for water reabsorption in the kidneys.2 Hence, AVP decreases free water excretion, bringing plasma osmolality back to normal levels. In heart failure, increased osmotic AVP release as well as non-osmotic stimuli may contribute to elevated AVP levels.3,4 Indeed, compared with healthy volunteers, patients with heart failure demonstrate a more pronounced rise in plasma AVP when given the same osmotic load.5 In addition, it is well known that baroreceptor activity and angiotensin II, both up-regulated in heart failure, increase AVP release irrespective of plasma osmolality values.2 Yet, surprisingly little is known about the actual relationship between AVP levels, plasma osmolality, and decongestive therapy in heart failure, especially in the current treatment era with neurohumoral blockers. The post-hoc analysis from the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) trial reported by Vaduganathan et al. in this issue of the journal therefore presents a welcome addition to the literature.6 In the EVEREST trial, patients presenting with reduced left ventricular ejection fraction and clear signs of volume overload were randomised to tolvaptan, a selective V2 receptor antagonist producing increased free water excretion (i.e. aquaresis), or matching placebo.7 The overall results of the trial showed a significantly greater reduction in body weight with tolvaptan, as well as