Changes in intracellular Na⁺ in heart failure following SERCA knockout – more of a solution or more of a problem?

One of the difficulties in understanding and treating heart failure (HF) is that it involves many structural, molecular and physiological defects (Bers, 2006). Diastolic and systolic dysfunction arise from distinct defects that may or may not contribute to disease development in an individual patient. For example, downregulation of sarcoplasmic/endoplasmic reticulum Ca²⁺-ATPase (SERCA) has been reported in HF and the level of SERCA expression was related to both type and severity of HF, so that variability in expression would be expected among a mixed patient population (Hasenfuss et al. 1999). Reduced SERCA means that less Ca²⁺ is taken up into the SR at a slower rate so less Ca²⁺ is available for contraction (systolic dysfunction) and relaxation slows (diastolic dysfunction). Intracellular Na⁺ concentration ([Na⁺]_i) is increased in both experimental and clinical HF, possibly as a result of an increase in the late component of rapid Na⁺ current, reduced Na⁺, K⁺-ATPase (NKA) expression/activity and increased Na⁺–Ca²⁺ exchange (NCX) expression/activity. This increase in diastolic [Na⁺]_i might maintain contractility by offsetting the negative inotropic consequences of reduced SERCA function. However, there is a cost to this mechanism of inotropic compensation in the form of increased [Ca²⁺]_i which contributes to slower relaxation and possibly triggered arrhythmias.

In a recent issue of The Journal of Physiology, Louch et al. (2010) investigated the mechanisms by which excitation–contraction coupling compensates for a conditional knock-out of SERCA in a mouse model of HF. As SERCA levels decline, the myocyte must compensate for the loss of its normal means of removing Ca²⁺ from the cytoplasm. The initial response was an increase in NCX expression along with increases in the L-type Ca²⁺ channel protein and current, providing the means by which trans-sarcolemmal Ca²⁺ entry is increased (activating contraction and maintaining cardiac output) and by which this extra Ca²⁺ is removed from the cell in the face of a non-functional SR. However, things become more complicated in the prolonged absence of SERCA as HF develops and additional compensatory changes occur as both systolic and diastolic dysfunction develop. These involve reduced expression of both α1 and α2 isoforms of NKA, leading to reduced Na⁺ removal and a resultant increase in resting [Na⁺]_i. The authors demonstrate quite convincingly that this Na⁺ accumulation in itself contributes to slower relaxation (via reduced Ca²⁺ efflux through the NCX) and therefore to diastolic dysfunction. This is an interesting and potentially important observation about how specific molecular changes affect the integrative physiology of cardiac function and contribute to the development of a specific disease state (HF). Curiously, the authors found no associated change in diastolic [Ca²⁺] although no data were presented addressing this point nor was there any discussion of how this could be.

Questions remain about why these particular forms of compensation occur and, of course, whether or not changes in mouse also occur in human HF. It is not clear why expression of NKA overall and/or specific isoforms are reduced in response to SERCA deletion. NKA expression is also decreased in human HF but there are likely to be marked differences in both NKA expression levels and the balance of isoform expression in humans where NKA expression is comprised mostly of α2 and α3 with little α1 expression (Wasserstrom & Aistrup, 2005). Moreover, the fact that late I_Na is increased in most HF models as well as in humans (Sossalla et al. 2008) means that [Na⁺]_i regulation is likely to play a critical role in HF onset and severity, depending on when changes occur in Na⁺ current kinetics, NKA and NCX expression and a multitude of other defects in contractile filaments, mitochondrial function, reactive oxygen species generation and so forth. It appears this interesting compensatory mechanism develops in response to a specific molecular defect and is initially able to deal effectively with altered physiological function but then becomes less a part of the solution and becomes more a part of the problem.