Less Na/H-exchanger to treat heart failure: a simple solution for a complex problem?

See article by Baartscheer et al.[1](pages 83–92) in this issue. Heart failure is one of the major causes of mortality and morbidity in the western world. Enormous investments have been made for researching the treatment of this disease with the aim of reconstructing the chain of events at the organ, cellular, and molecular levels that leads to cardiac hypertrophy and/or heart failure. This challenge is extremely complex because almost every cellular and molecular system is affected in heart failure. These modifications can be a cause or a consequence of heart failure, can be compensatory or detrimental, or can be simply epiphenomena. The ideal target for heart failure research is the identification of key factors that are commonly activated by the underlying diseases and are responsible for inducing the functional changes. Normalisation of these key factors would restore cardiac function or, at the very least, prevent further dysfunction. There is now evidence that one of these key factors is the Na+/H+-exchanger (NHE-1). Several studies have now shown that inhibiting the NHE-1 in heart failure is beneficial. In the present issue of Cardiovascular Research the article by Baartscheer et al. [1] presents further evidence for this effect. Investigations into the role of the NHE-1 in cardiac disease have been examined under two main clinical scenarios: (1) in the setting of ischaemia/reperfusion; (2) during progression from hypertrophy to heart failure. In many studies heart failure has developed following myocardial infarction, itself a result of ischaemic damage to the myocardium. During ischaemia the NHE-1 is the major route for adaptation and recovery from the acidosis following an ischaemia/reperfusion injury period. Intracellular acidosis is the primary stimulus for activation of the NHE-1. There are, however, many pathways which may also lead to NHE-1 activation. Stimulation of the NHE-1 can occur via endothelin-1, angiotensin II, α1-adrenergic agonists, thrombin, and growth factors or cardiac insult through H2O2 production and reduced ATP levels [2]. Activation of these pathways or ischaemia and ischaemia/reperfusion lead to increasing levels of NHE-1 mRNA, which can be attenuated by NHE-1 inhibition with cariporide [3]. Evidence suggests that the NHE-1 may have an important role in regulating cell hypertrophy. For example, NHE-1 inhibition prevented angiotensin II-induced vascular smooth muscle cell growth [4]. In cardiac cells, NHE-1 activity plays a permissive role in hypertrophic growth induced by G protein-coupled receptor signalling (through angiotensin II, endothelin, and α1-adrenergic agonists). Specific inhibition of the NHE-1, in the presence of these agonists, attenuates cell hypertrophy [5,6]. It has also been shown that there is a protective effect of BIIB722, another NHE-1 inhibitor, on left ventricular function in a non-ischaemic pacing model of heart failure [7]. The ability of NHE-1 inhibitors to block a variety of stimuli for hypertrophy suggests that the NHE-1 could be a common key factor of cardiac cell hypertrophy [2,5,8]. Previous work by Baartscheer et al. [9] has shown that acute application of cariporide on isolated cardiac myocytes could ameliorate disturbances to calcium handling in a volume- and pressure-overload model of heart failure. The same authors now examine the effect of chronic treatment with cariporide on Ca2+ homeostasis during the development of heart failure [1]. They find that cariporide attenuates hypertrophy and prevents ionic cellular remodelling when administered during the development of heart failure. They conclude that this treatment may decrease the risk of heart failure in some patients. The effectiveness of NHE-1 inhibitors after heart failure has developed still requires further research. For the last two decades it has been known that dysregulation of intracellular [Ca2+] is an important cause of functional impairment in heart failure. Cardiac myocytes have smaller and prolonged Ca2+transients, leading to systolic and diastolic dysfunction [10]. The expression and function of all the major Ca2+ regulatory mechanisms–SERCA, phospholamban, the ryanodine receptor and the Na+/Ca2+-exchanger–are altered in heart failure [11]. Moreover, normalisation of these mechanisms with either pharmacological or gene therapy restores the normal functional phenotype of the myocytes (e.g. Refs. [12–14]). More recently Na+ dysregulation has been described in heart failure and linked to the pathophysiology of the disease [15]. The study by Baartscheer et al. [1] addresses this point by suggesting that the beneficial effects of NHE-1-inhibitors observed are due to normalisation of [Na+]i. However, they also found critical effects on Ca2+ regulation: Ca2+ transients and SR Ca2+ handling did not change in cariporide-treated myocytes. These findings were used as part of the evidence that cariporide prevents cardiac dysfunction. The combined observations of normalisation of both [Na+]i and [Ca2+]i in heart failure by cariporide have a number of implications: (1) the increase in [Na+]i in heart failure is predominantly mediated by increased function of the NHE-1. This was shown by the same authors previously [9], but the mechanisms that bring about this increase remain unclear [15]. After NHE-1 activation other Na+ regulatory mechanisms could compensate for a [Na+]i increase. However, these mechanisms do not seem to be effective in maintaining Na+ homeostasis, may also be affected in heart failure, and could be considered potential therapeutic targets. More research into the role of these mechanisms is required; (2) Baartscheer et al. [9] speculate that decreasing [Na+]i would reduce diastolic [Ca2+]i (via Na+/Ca2+-exchanger), thus favouring improvement of SR Ca2+ regulation. However, altered expression of SERCA/phospholamban and hyperphosphorylation of ryanodine receptors occur in heart failure, and a reduction in [Na+]i per se without normalisation of these proteins would not be expected to normalise SR Ca2+ handling. Whether NHE-1 inhibition has a direct effect on SR Ca2+ regulatory protein expression and/or phosphorylation requires further investigation; (3) other researchers have also achieved restoration or normalisation of cardiac function in models of heart failure by targeting single mechanisms involved in [Ca2+]i rather than [Na+]i regulation (such as overexpressing SERCA, inhibiting phospholamban, and even inhibiting the Na+/Ca2+-exchanger [12–14]). It is possible to speculate that the key factor that brings about functional changes is not NHE-1 but [Ca2+]i itself. [Ca2+]i is a powerful mediator of cardiac hypertrophy [16] and its reduction may result in normalisation or prevention of dysfunction. NHE-1 inhibition could therefore be effective via a mechanism that also reduces cellular [Ca2+]i via the Na+/Ca2+-exchanger in the presence of reduced [Na+]i. In conclusion, inhibition of the [Na+] increase, via NHE-1 inhibitors, may represent a useful strategy for the treatment of heart failure. Whether the mechanisms underlying this approach could directly explain dysfunction in heart failure or represent yet another step in the understanding of a complex problem remains to be unresolved.