CrossTalk opposing view: The late sodium current is not an important player in the development of diastolic heart failure (heart failure with a preserved ejection fraction)

Diastolic heart failure (also referred to as heart failure with preserved ejection fraction (HFpEF)) is considered when the signs and symptoms of heart failure develop in response to left ventricular (LV) diastolic dysfunction without a significant decrease in the LV ejection fraction (McMurray et al. 2012). Currently, questions outweigh answers for the molecular background of HFpEF, mostly because the clinical picture of HFpEF is complicated by co-morbidities, various haemodynamic conditions, and uncertain therapeutic interventions. Nevertheless, demographic and preclinical investigations now implicate roles for hypertension, obesity, diabetes, and concentric LV hypertrophy in the pathophysiology of HFpEF (Edelmann et al. 2011; Shah & Solomon, 2012; Paulus & Tschope, 2013).

Ventricular filling depends on a dynamic interplay between the heart and the vascular system, and impairments in diastolic filling/ventricular suction occur in response to abnormalities in ventriculo-arterial coupling, arterial wave reflections, and/or atrio-ventricular pressure gradients in association with impaired cardiomyocyte relaxation (De Keulenaer & Brutsaert, 2011). Cardiomyocyte contractions and relaxations are controlled by Ca²⁺-regulated cardiac myofilaments. Therefore, ventricular performance is the function of the magnitude and kinetic aspects of the intracellular Ca²⁺ transient (Bers, 2000). In this context, an increased late sodium current (I_Na,L) may prolong action potentials (leading to increased Ca²⁺ entry via the L-type Ca²⁺ current), and it has the potential to diminish the trans-sarcolemmal Na⁺ gradient thereby rendering cytoplasmic Ca²⁺ removal (through the Na⁺–Ca²⁺ exchange mechanism) ineffective (Bers et al. 2003). These processes may then result in an inappropriately high intracellular Ca²⁺ concentration during diastole, thus limiting myocardial relaxation (Hasenfuss et al. 1999; Pieske & Houser, 2003). Indeed, increases in I_Na,L have been documented in failing cardiomyocytes (Maltsev et al. 1998; Undrovinas et al. 2010). Moreover, an intracellular signalling mechanism, involving Ca²⁺–calmodulin-dependent protein kinase (CaMKII)-mediated cardiac Na⁺ channel phosphorylation, and consequently enhanced I_Na,L, have been also proposed for the failing heart (Wagner et al. 2006). Interestingly, blocking the CaMKII signalling cascade improved contractility in myocardial preparations of failing human hearts (Sossalla et al. 2010). Moreover, inhibition of I_Na,L effectively reversed diastolic dysfunction caused by the overexpression of CaMKIIδ_C in a transgenic murine model of heart failure (Sossalla et al. 2011).

In summary, it has been hypothesised that: (1) the extent of ventricular relaxation is influenced by the magnitude of I_Na,L which can be augmented by CaMKII-dependent phosphorylation during pathological conditions (Wagner et al. 2006; Maltsev & Undrovinas, 2008); (2) increases in I_Na,L leads primarily to impairments in passive (or late-phase) ventricular relaxation (as opposed to active, or early-phase relaxation) (Sossalla et al. 2008; Maier et al. 2013); and consequently (3) increased I_Na,L can be regarded as a potential mediator of diastolic dysfunction in the failing heart (Maltsev & Undrovinas, 2008; Sossalla et al. 2011).

The above proposal is supported by experimental studies, carried out under various experimental arrangements in different species, where pharmacological inhibition of I_Na,L was achieved most frequently by ranolazine (Fraser et al. 2006; Rastogi et al. 2008; Sossalla et al. 2008; Zhang et al. 2008; Hwang et al. 2009; Sossalla et al. 2011). Collectively, these investigations make a strong case for the concordant changes in increased intracellular Na⁺ and Ca²⁺ levels with myocardial diastolic dysfunction, and at high heart rates in particular. However, the proposed selective role for I_Na,L in the passive (i.e. sarcoplasmic reticulum-independent) phase of ventricular relaxation, but not in the active (i.e. sarcoplasmic reticulum-dependent) phase of ventricular relaxation is as a concept not self-explanatory (Sossalla et al. 2008; Maier et al. 2013). One expects the participation of I_Na,L in the complex balance of intracellular Na⁺ and Ca²⁺ homeostases to certainly affect early active relaxation kinetics, which clearly depend on sarcoplasmic Ca²⁺ loading. Moreover, certain limitations inherent to the employed experimental arrangements leave additional uncertainties with respect to the extrapolation to HFpEF myocardium. For example, intracellular Na⁺ level in cardiomyocytes of small rodents is considered to be significantly higher than that of humans, and several other characteristics of excitation–contraction coupling exhibit also profound species dependencies (Bers et al. 2003; Pieske & Houser, 2003). Moreover, frequency-dependent responses might be complicated by diffusion-related inequalities in the compositions of extracellular and intracellular spaces between marginal and core zones of multicellular muscle strip preparations ex vivo (Schouten & ter Keurs, 1986; Hasenfuss et al. 1999; Sossalla et al. 2008). Importantly, CaMKII inhibition improved systolic contractility, but it did not affect diastolic function (Sossalla et al. 2010), suggesting that CaMKII-dependent Na⁺ channel phosphorylation might be counterbalanced by CaMKII-mediated phosphorylation of other key molecules of intracellular Ca²⁺ homeostasis in the failing human heart (Anderson et al. 2011). CaMKII activation has been mostly associated with adverse cardiac remodelling, including ventricular dilatation (Anderson et al. 2011), whereas the prevalent phenotype for HFpEF patients is concentric ventricular hypertrophy without significant ventricular dilatation (Paulus & Tschope, 2013). Taken together, it is still to be demonstrated (preferably at the single cell level) whether CaMKII-up-regulated I_Na,L increases intracellular Na⁺ levels and (via altered Na⁺–Ca²⁺ exchange function) Ca²⁺ levels in human cardiomyocytes, and whether this is directly responsible for diastolic dysfunction in HFpEF patients.

Of note, ranolazine inhibits a number of ionic currents other than I_Na,L at its therapeutic concentration (Antzelevitch et al. 2004) including the L-type Ca²⁺ current, and hence it would be interesting to see if the beneficial effects of ranolazine on diastolic function were related solely to the inhibition of I_Na,L, or to some degree to other key players of intracellular Ca²⁺ handling and/or myofilament Ca²⁺ sensitivity (Lovelock et al. 2012). Finally, ranolazine – as a putative partial fatty acid oxidation inhibitor – may limit lactate production and H⁺ accumulation through stimulating glucose oxidation, thereby affecting intracellular Ca²⁺ homeostasis, myofilament Ca²⁺ sensitivity and ultimately myocardial relaxation (Sabbah et al. 2002; Rastogi et al. 2008). Perhaps, antagonists of I_Na,L other than ranolazine with distinct pharmacological profiles could address the concerns adherent to the specificity of ranolazine.

Clinical observations with the strategy of I_Na,L inhibition for HFpEF patients are scarce, based on relatively small samples sizes, and generally speaking, not strongly supportive for a central role of I_Na,L in HFpEF (Moss et al. 2008). For example, in the recent ALI-DHF (RAnoLazIne for the treatment of Diastolic Heart Failure) Phase IIa proof-of-concept study where the acute effects of ranolazine on haemodynamics and diastolic function in outpatients with chronic HFpEF were studied, ranolazine therapy was accompanied by only small reductions in invasively determined LV filling pressures, without parallel changes in LV relaxation kinetics (Maier et al. 2013).

In summary, HFpEF is a complex syndrome that develops in a patient population with many, especially metabolic comorbidities, where cardiac and/or vascular pathophysiological changes are seen in combination with LV diastolic dysfunction. Currently available preclinical and clinical data on I_Na,L do not exclude alternative proposals (e.g. myocardial fibrosis/deposition of matricellular proteins, sarcomeric myofilament protein alterations) for the explanation of impaired myocardial relaxation/increased ventricular stiffness commonly associated with HFpEF (Borbely et al. 2005; van Heerebeek et al. 2012). Hence, it is still to be established in which patient population and by which (systemic and local) signalling mechanisms increased I_Na,L could dominate the complex picture of HFpEF pathophysiology in humans.

Taken together, a casual role of I_Na,L in HFpEF could be made more compelling by including more specific inhibitors than ranolazine, by concentrating on single human cardiomyocytes, and perhaps by including animal models where genetically modulated Na⁺ channels would allow either up- or down-regulation of Na⁺ current inactivation.

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Competing interests

None declared.

Funding

Supported by grants from the European Commission (FP7-Health-2010; MEDIA-261409), by the Social Renewal Operational Programme (TÁMOP-4.2.2.A-11/1/KONV-2012–0045) and by Hungarian Scientific Research Fund (OTKA K 109083 and OTKA PD 108614) and co-financed by the European Social Fund in the framework of TÁMOP 4.2.4. A/2-11-1-2012-0001 ‘National Excellence Program’.