Hypothesis: Potassium sparing by angiotensin and aldosterone inhibitors preserves skeletal muscle mass in chronic heart failure

Cachexia complicates many chronic diseases. In chronic or congestive heart failure (CHF), cachexia independently contributes to decreased survival. Although diuretics have long been part of standard treatment of CHF, the addition of angiotensin and aldosterone antagonists to the standard treatment regimen has considerably improved the outcome of CHF. Both loop diuretics and the up‐regulation of the renin–angiotensin–aldosterone system caused by CHF induce loss of total body potassium (TBK).


Introduction
Cachexia is a serious complication of many chronic diseases, such as cancer, liver cirrhosis, and heart failure. 1,2 The loss of skeletal muscle in patients with chronic or congestive heart failure (CHF) is related to impaired survival, independent of other factors. 1 As CHF is currently the third most common chronic co-morbidity, cachexia constitutes a public health issue. 3 Prevention of the loss of muscle mass in CHF might improve outcome. We propose a new hypothesis considering an important role of the loss of potassium in cardiac cachexia through both the activation of the renin-angiotensinaldosterone system (RAAS) and the use of loop diuretics and the potential protective effect of angiotensin and aldosterone inhibition on skeletal muscle mass.

Chronic heart failure
CHF remains one of the most common, disabling and deadly chronic diseases, with a quality of life lower than that of many other chronic diseases. 4 The pathophysiology of CHF is complex and multifactorial, with interaction of immune, metabolic, and neurohormonal factors, which eventually facilitate a chronic catabolic state. 3 The impaired cardiac function in CHF leads to neurohormonal activation through the sympathetic nervous system, RAAS, and the natriuretic peptide system. 3,5 The up-regulation of both epinephrine and norepinephrine causes a catabolic shift, leading to a higher resting energy expenditure in CHF patients. However, up-regulation of the RAAS in CHF has long been seen as the inducer of cachexia, as both angiotensin II and aldosterone are associated with muscle wasting 6 ( Figure 1). Currently, it is thought that angiotensin II causes muscle wasting through multiple mechanisms, such as increased oxidative stress, increased protein breakdown, reduced appetite, impaired energy balance, and inhibition of satellite cell function and muscle regeneration. 3 Aldosterone is associated with both cardiac and skeletal muscle loss and myocyte apoptosis. 6 It also promotes the retention of sodium, loss of potassium and magnesium, sympathetic activation, parasympathetic inhibition, and vascular and myocardial fibrosis. 5 The management of CHF has greatly improved over the last decades. Established components of CHF treatment are loop diuretics, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and mineralocorticoid receptor antagonists (MRAs). Loop diuretics are used to prevent fluid and sodium overload in CHF patients. Both ACE inhibitors and ARBs reduce angiotensin II and therefore lead to improvement in symptoms and prolonged survival in CHF patients. 6 In patients with symptomatic heart failure, addition of the MRA spironolactone leads to an additional reduction of both morbidity and mortality. 7

Total body potassium
From an evolutionary point of view, humans have never been confronted with potassium-scarce diets. Therefore, very limited mechanisms exist to preserve potassium, in contrast to sodium.
Potassium is the major cation of the intracellular compartment. A large part of the total body potassium (TBK) resides in skeletal muscle, and radionuclear TBK quantification can be used to measure muscle mass. 8 Cachexia thus logically leads to a reduction in TBK, 9,10 which has been observed in other cachectic patient groups. During critical illness, a reduction in both the intracellular volume and TBK is seen. 11,12 Heart failure itself is associated with a loss of TBK 13 ( Figure  1). This is not only because of the loss of muscle mass but also because of intracellular potassium depletion, 14 underscoring the constant stress that the intracellular compartment is exposed to in this situation. The potassium depletion in CHF is partly explained by up-regulation of the RAAS and therefore increased aldosterone secretion. This loss can be exacerbated by the treatment of CHF with diuretics. 9 Several studies have shown that long-term treatment with conventional loop diuretics such as furosemide and bumetanide leads to a decrease in intracellular potassium concentration in skeletal muscle cells. 15,16 An important part of resting energy expenditure is devoted to the maintenance of Na + /K + gradients. 17 The constant extra work to maintain these gradients, resulting from mild hypokalaemia caused by CHF itself and diuretics, will place additional energetic demands on the already often poorly perfused skeletal muscle and other tissues. Because it is essential that the intracellular potassium concentration be held above a minimal concentration, a cell only has one strategy left when faced with ongoing potassium loss to the extracellular space, namely, to reduce its volume or to go into apoptosis.
A key part of the CHF treatment is targeted against the up-regulation of the RAAS and thus may be beneficial in the prevention of loss of TBK and muscle mass (Figure 1). Use of ACE inhibitors is associated with a reduction in weight loss in cachectic CHF patients and delays the development of cachexia by 8 months. 1,18 ARBs might also have a favourable effect on the cachectic effects of RAAS, as found in different mouse models of myopathy that demonstrated increased muscle strength and muscle regenerative ability after ARB treatment. 18 Several studies show that in both CHF and liver cirrhosis patients, when spironolactone is added to conventional treatment this results in a rise in intracellular potassium, even when it was first depleted. 2, 19 Intracellular potassium even Figure 1 Schematic depiction of the proposed hypothesis. CHF induces up-regulation of the RAAS, hereby increasing the loss of TBK. CHF treatment with diuretics further aggravates this loss. The loss of TBK leads to loss of muscle mass and vice versa. We propose that part of the beneficial effect of angiotensin and aldosterone inhibition results from a preservation of TBK and consequently muscle mass. ACEi, angiotensin-converting enzyme inhibitor, ARB, angiotensin receptor blocker; CHF, chronic (or congestive) heart failure; MRA, mineralocorticoid receptor antagonist; RAAS, renin-angiotensin-aldosterone system; TBK, total body potassium.
increased to a concentration similar to that of healthy controls. 2 Furthermore, it has been shown that spironolactone increases exercise tolerance in CHF patients, also suggesting that this increase in intracellular potassium might impact on the quality of muscle. 20 An increase in serum creatinine is often observed after addition of an MRA, and this only underscores the beneficial effect of angiotensin and aldosterone inhibition on skeletal muscle. 19

Preservation of total body potassium and prevention of cachexia
CHF is accompanied by (intracellular) potassium depletion. Interestingly, nobody has linked this potassium depletion and the success of the angiotensin and aldosterone inhibitors in the treatment of CHF. The beneficial effect of MRAs and the already aldosterone-blocking ACE inhibitors or ARBs may very well be dual: in addition to further counteracting aldosterone , this cocktail may also be muscle sparing ( Figure  1). We postulate that the persistent loss of intracellular potassium leads to loss of muscle mass in CHF patients and vice versa.

Testing the hypothesis
Although several studies have shown that the potassium concentration rises in skeletal muscle after starting MRAs, no study has yet directly demonstrated the relation between intracellular potassium loss and muscle wasting.
It is difficult to assess TBK. The gold standard for TBK is 40 K scintigraphy, which is a cumbersome and expensive method. However, the absolute value of TBK is not necessarily needed to determine alterations in TBK. Potassium balances might be a much easier and reliable way to assess changes in TBK. 10,12 Monitoring the amount of muscle loss and potassium balances in CHF patients would provide us with more information regarding the association between potassium loss and muscle wasting. The increased resting energy expenditure that is needed in CHF patients to maintain the Na + /K + gradient might be assessed with indirect calorimetry or fluorodeoxyglucose positron emission tomography scanning.
However, to our knowledge, no such studies have been conducted in potassium-depleted patients. Because the effect of angiotensin and aldosterone inhibition has not been directly tested on skeletal muscle preservation and function, this should also be further studied.

Implications
This hypothesis provides an additional explanation of the beneficial effect of angiotensin and aldosterone inhibitors on muscle mass. ACE inhibitors, ARBs, and MRAs might also be beneficial in other patient groups, for example, other chronic diseases leading to cachexia, older patients, and critically ill patients. As our society ages, the prevalence of chronic diseases will rise. This makes cachexia a major public health problem, requiring treatments that minimize muscle wasting.
Monitoring potassium balances is an easy and reliable way to monitor skeletal muscle loss and thereby the possible effectiveness of treatment. We therefore propose that future CHF studies should address potassium balances together with monitoring of muscle mass.