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 (INa,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 INa,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 INa,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 INa,L effectively reversed diastolic dysfunction caused by the overexpression of CaMKIIδC 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 INa,L which can be augmented by CaMKII-dependent phosphorylation during pathological conditions (Wagner et al. 2006; Maltsev & Undrovinas, 2008); (2) increases in INa,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 INa,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 INa,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 INa,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 INa,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 INa,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 INa,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 INa,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 INa,L other than ranolazine with distinct pharmacological profiles could address the concerns adherent to the specificity of ranolazine. Clinical observations with the strategy of INa,L inhibition for HFpEF patients are scarce, based on relatively small samples sizes, and generally speaking, not strongly supportive for a central role of INa,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 INa,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 INa,L could dominate the complex picture of HFpEF pathophysiology in humans. Taken together, a casual role of INa,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. Readers are invited to give their views on this and the accompanying CrossTalk articles in this issue by submitting a brief comment. Comments may be posted up to 6 weeks after publication of the article, at which point the discussion will close and authors will be invited to submit a ‘final word'. To submit a comment, go to http://jp.physoc.org/letters/submit/jphysiol;592/3/415 Zoltán Papp is a professor of clinical physiology and head of a research division at the Institute of Cardiology, University of Debrecen, Hungary. He also serves as a vice-dean at the Medical Faculty of the University of Debrecen, and as the chairman of the Basic Science Section of the Heart Failure Association of the European Society of Cardiology. His research interests focuses on the contractile function of cardiomyocytes and on its pharmacological modification. Walter J. Paulus is a professor of physiology at the department of physiology, Institute for Cardiovascular Research, VU University Medical Center Amsterdam, the Netherlands, and is the associate director of the Cardiovascular Center, O.L.V. Hospital, Aalst, Belgium. He also acts as the coordinator of the European Commission FP7 Health Large Collaborative Project on Diastolic Heart Failure (MEDIA). His research concentrates on the pathophysiology, diagnosis and potential therapy of diastolic heart failure. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. None declared. 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’.