Showing papers by "Walter Paulus published in 2014"

New strategies for heart failure with preserved ejection fraction: the importance of targeted therapies for heart failure phenotypes

Abstract: The management of heart failure with reduced ejection fraction (HF-REF) has improved significantly over the last two decades. In contrast, little or no progress has been made in identifying evidence-based, effective treatments for heart failure with preserved ejection fraction (HF-PEF). Despite the high prevalence, mortality, and cost of HF-PEF, large phase III international clinical trials investigating interventions to improve outcomes in HF-PEF have yielded disappointing results. Therefore, treatment of HF-PEF remains largely empiric, and almost no acknowledged standards exist. There is no single explanation for the negative results of past HF-PEF trials. Potential contributors include an incomplete understanding of HF-PEF pathophysiology, the heterogeneity of the patient population, inadequate diagnostic criteria, recruitment of patients without true heart failure or at early stages of the syndrome, poor matching of therapeutic mechanisms and primary pathophysiological processes, suboptimal study designs, or inadequate statistical power. Many novel agents are in various stages of research and development for potential use in patients with HF-PEF. To maximize the likelihood of identifying effective therapeutics for HF-PEF, lessons learned from the past decade of research should be applied to the design, conduct, and interpretation of future trials. This paper represents a synthesis of a workshop held in Bergamo, Italy, and it examines new and emerging therapies in the context of specific, targeted HF-PEF phenotypes where positive clinical benefit may be detected in clinical trials. Specific considerations related to patient and endpoint selection for future clinical trials design are also discussed.

Induction of self awareness in dreams through frontal low current stimulation of gamma activity

Abstract: Recent findings link fronto-temporal gamma electroencephalographic (EEG) activity to conscious awareness in dreams, but a causal relationship has not yet been established. We found that current stimulation in the lower gamma band during REM sleep influences ongoing brain activity and induces self-reflective awareness in dreams. Other stimulation frequencies were not effective, suggesting that higher order consciousness is indeed related to synchronous oscillations around 25 and 40 Hz.

Ceiling Effects Prevent Further Improvement of Transcranial Stimulation in Skilled Musicians

Abstract: The roles of the motor cortex in the acquisition and performance of skilled finger movements have been extensively investigated over decades. Yet it is still not known whether these roles of motor cortex are expertise-dependent. The present study addresses this issue by comparing the effects of noninvasive transcranial direction current stimulation (tDCS) on the fine control of sequential finger movements in highly trained pianists and musically untrained individuals. Thirteen pianists and 13 untrained controls performed timed-sequence finger movements with each of the right and left hands before and after receiving bilateral tDCS over the primary motor cortices. The results demonstrate an improvement of fine motor control in both hands in musically untrained controls, but deterioration in pianists following anodal tDCS over the contralateral cortex and cathodal tDCS over the ipsilateral cortex compared with the sham stimulation. However, this change in motor performance was not evident after stimulating with the opposite montage. These findings support the notion that changes in dexterous finger movements induced by bihemispheric tDCS are expertise-dependent.

Impact of transcranial direct current stimulation on fatigue in multiple sclerosis

Abstract: Purpose: Fatigue is a frequent and difficult to treat symptom affecting patients with multiple sclerosis (MS) with a profound negative impact on quality of life. Fatigue has been associated with functional and structural abnormalities of the frontal cortex, including frontal hypo-activation. The aim of this exploratory study was to assess whether fatigue symptoms can be reduced by excitability-enhancing anodal transcranial direct current stimulation (tDCS). Methods: In this sham-controlled, double-blind intervention study, tDCS was applied over the left prefrontal cortex of MS patients with fatigue for five consecutive days. Symptoms were tracked for 1 month via questionnaires. Lesion load at baseline was calculated for each patient and correlated with fatigue levels and responsiveness to stimulation. Results: In the whole group analysis the scores of the fatigue scales were not altered by tDCS. However, in an exploratory analysis we found a correlation between response to the stimulation regarding subjectively perceived fatigue and lesion load in the left frontal cortex: patients responding positively to anodal tDCS had higher lesion load, compared to non-responding patients. Conclusion: We conclude that in patient subgroups discernible by specific morphological alterations, tDCS may be a tool for MS fatigue management.

Nonlinear Dose-Dependent Impact of D1 Receptor Activation on Motor Cortex Plasticity in Humans

Abstract: The neuromodulator dopamine plays an important role in synaptic plasticity. The effects are determined by receptor subtype specificity, concentration level, and the kind of neuroplasticity induced. D1-like receptors have been proposed to be involved in cognitive processes via their impact on plasticity. Cognitive studies in humans and animals revealed a dosage-dependent effect of D1-like receptor activation on task performance. In humans, D1-like receptor activation re-establishes plasticity under D2 receptor block. However, a dosage-dependent effect has not been explored so far. To determine the impact of the amount of D1-like receptor activation on neuroplasticity in humans, we combined sulpiride, a selective D2 receptor antagonist, with the dopamine precursor l-DOPA (25, 100, and 200 mg) or applied placebo medication. The impact on plasticity induced by anodal and cathodal transcranial direct current stimulation (tDCS) was compared with the impact on plasticity induced by excitatory and inhibitory paired associative stimulation (PAS) at the primary motor cortex of healthy humans. Stimulation-generated cortical excitability alterations were monitored by transcranial magnetic stimulation-induced motor-evoked potential amplitudes. D1-like receptor activation produced an inverted U-shaped dose–response curve on plasticity induced by both facilitatory tDCS and PAS. For excitability-diminishing tDCS and PAS, aftereffects were abolished or converted trendwise into facilitation. These data extend findings of dose-dependent inverted U-shaped effects of D1 receptor activation on neuroplasticity of the motor cortex.

Surmounting retraining limits in musicians' dystonia by transcranial stimulation.

Abstract: Objective Abnormal cortical excitability is evident in various movement disorders that compromise fine motor control. Here we tested whether skilled finger movements can be restored in musicians with focal hand dystonia through behavioral training assisted by transcranial direct current stimulation to the motor cortex of both hemispheres. Methods The bilateral motor cortices of 20 pianists (10 with focal dystonia, 10 healthy controls) were electrically stimulated noninvasively during bimanual mirrored finger movements. Results We found improvement in the rhythmic accuracy of sequential finger movements with the affected hand during and after cathodal stimulation over the affected cortex and simultaneous anodal stimulation over the unaffected cortex. The improvement was retained 4 days after intervention. Neither a stimulation with the reversed montage of electrodes nor sham stimulation yielded any improvement. Furthermore, the amount of improvement was positively correlated with the severity of the symptoms. Bihemispheric stimulation without concurrent motor training failed to improve fine motor control, underlining the importance of combined retraining and stimulation for restoring the dystonic symptoms. For the healthy pianists, none of the stimulation protocols enhanced movement accuracy. Interpretation These results suggest a therapeutic potential of behavioral training assisted by bihemispheric, noninvasive brain stimulation in restoring fine motor control in focal dystonia. ANN NEUROL 2014;75:700–707

Left ventricular diastolic dysfunction and myocardial stiffness in diabetic mice is attenuated by inhibition of dipeptidyl peptidase 4.

Abstract: Aims Obesity and Type 2 diabetes mellitus (DM) induce left ventricular (LV) diastolic dysfunction, which contributes to an increasing prevalence of heart failure with a preserved LV ejection fraction. We investigated the effects of sitagliptin (SITA), an inhibitor of dipeptidylpeptidase-4 (DPP-4) and anti-diabetic drug, on LV structure and function of obese mice with Type 2 DM. Methods and results Obese Type 2 diabetic mice (Leprdb/db, BKS.Cg-Dock7m+/+ Leprdb/J), displaying increased cardiomyocyte and LV stiffness at the age of 16 weeks, were treated with SITA (300 mg/kg/day) or vehicle for 8 weeks. SITA severely impaired serum DPP-4 activity, but had no effect on glycaemia. Invasive haemodynamic recordings showed that SITA reduced LV passive stiffness and increased LV stroke volume; LV end-systolic elastance remained unchanged. In addition, SITA reduced resting tension of isolated single cardiomyocytes and intensified phosphorylation of the sarcomeric protein titin. SITA also increased LV concentrations of cGMP and increased activity of protein kinase G (PKG). In vitro activation of PKG decreased resting tension of cardiomyocytes from vehicle-treated mice, but had no effect on resting tension of cardiomyocytes from SITA-treated mice. Conclusions In obese Type 2 diabetic mice, in the absence of hypoglycaemic effects, inhibition of DPP-4 decreases LV passive stiffness and improves global LV performance. These effects seem at least partially mediated by stimulatory effects on the myocardial cGMP–PKG pathway and, hence, on the phosphorylation status of titin and the hereto coupled cardiomyocyte stiffness modulus.

Dosage-Dependent Effect of Dopamine D2 Receptor Activation on Motor Cortex Plasticity in Humans

Abstract: The neuromodulator dopamine plays an important role in synaptic plasticity. The effects depend on receptor subtypes, affinity, concentration level, and the kind of neuroplasticity induced. In animal experiments, dopamine D2-like receptor stimulation revealed partially antagonistic effects on plasticity, which might be explained by dosage dependency. In humans, D2 receptor block abolishes plasticity, and the D2/D3, but predominantly D3, receptor agonist ropinirol has a dosage-dependent nonlinear affect on plasticity. Here we aimed to determine the specific affect of D2 receptor activation on neuroplasticity in humans, because physiological effects of D2 and D3 receptors might differ. Therefore, we combined application of the selective D2 receptor agonist bromocriptine (2.5, 10, and 20 mg or placebo medication) with anodal and cathodal transcranial direct current stimulation (tDCS), which induces nonfocal plasticity, and with paired associative stimulation (PAS) generating a more focal kind of plasticity in the motor cortex of healthy humans. Plasticity was monitored by transcranial magnetic stimulation-induced motor-evoked potential amplitudes. For facilitatory tDCS, bromocriptine prevented plasticity induction independent from drug dosage. However, its application resulted in an inverted U-shaped dose–response curve on inhibitory tDCS, excitability-diminishing PAS, and to a minor degree on excitability-enhancing PAS. These data support the assumption that modulation of D2-like receptor activity exerts a nonlinear dose-dependent effect on neuroplasticity in the human motor cortex that differs from predominantly D3 receptor activation and that the kind of plasticity-induction procedure is relevant for its specific impact.

Idiopathic-generalized epilepsy shows profound white matter diffusion-tensor imaging alterations.

Abstract: Objectives Idiopathic-generalized epilepsy (IGE) is currently considered to be a genetic disease without structural alterations on conventional MRI. However, voxel-based morphometry has shown abnormalities in IGE. Another method to analyze the microstructure of the brain is diffusion-tensor imaging (DTI). We sought to clarify which structural alterations are present in IGE and the most frequent subsyndrome juvenile myoclonic epilepsy (JME). Experimental design We studied 25 patients (13 IGE and 12 JME) and 44 healthy controls with DTI. Fractional anisotropy (FA), mean diffusivity (MD), axial and radial diffusivity (AD/RD) were calculated and group differences were analyzed using tract-based spatial statistics (TBSS). Additionally we performed a target-based classification of TBSS results based on the Freesurfer cortical regions. Principle observations TBSS showed widespread FA reductions as well as MD and RD increases in patients compared to controls. Affected areas were corpus callosum, corticospinal tract, superior and inferior longitudinal fasciculus and supplementary motor regions. No significant differences were found between JME and IGE subgroups. The target-based classification confirmed a particular involvement of the superior frontal gyrus (mesiofrontal area) in IGE/ME. Conclusions IGE and JME patients showed clear microstructural alterations in several large white matter tracts. Similar findings have been reported in rodent models of IGE. Previous, region-of-interest-based DTI studies may have under-estimated the spatial extent of structural loss associated with generalized epilepsy. The comparison of clinically defined JME and IGE groups revealed no significant DTI differences in our cohort. Hum Brain Mapp 35:3332–3342, 2014. © 2013 Wiley Periodicals, Inc.

Transcranial electrical stimulation modifies the neuronal response to psychosocial stress exposure

Abstract: Stress is a constant characteristic of everyday life in our society, playing a role in triggering several chronic disorders. Therefore, there is an ongoing need to develop new methods in order to manage stress reactions. The regulatory function of right medial-prefrontal cortex (mPFC) is frequently reported by imaging studies during psychosocial stress situations. Here, we examined the effects of inhibitory and excitatory preconditioning stimulation via cathodal and anodal transcranial direct current stimulation (tDCS) on psychosocial stress related behavioral indicators and physiological factors, including the cortisol level in the saliva and changes in brain perfusion. Twenty minutes real or sham tDCS was applied over the right mPFC of healthy subjects before the performance of the Trier Social Stress Test (TSST). Regional cerebral blood flow (rCBF) was measured during stimulation and after TSST, using pseudo-continuous arterial spin labeling (pCASL). Comparing the effect of the different stimulation conditions, during anodal stimulation we found higher rCBF in the right mPFC, compared to the sham and in the right amygdala, superior PFC compared to the cathodal condition. Salivary cortisol levels showed a decrease in the anodal and increase in cathodal groups after completion of the TSST. The behavioral stress indicators indicated the increase of stress level, however, did not show any significant differences among groups. In this study we provide the first insights into the neuronal mechanisms mediating psychosocial stress responses by prefrontal tDCS.

Facilitating myoelectric-control with transcranial direct current stimulation: a preliminary study in healthy humans.

Abstract: Background: Functional Electrical Stimulation (FES) can electrically activate paretic muscles to assist movement for post-stroke neurorehabilitation. Here, sensory-motor integration may be facilitated by triggering FES with residual electromyographic (EMG) activity. However, muscle activity following stroke often suffers from delays in initiation and termination which may be alleviated with an adjuvant treatment at the central nervous system (CNS) level with transcranial direct current stimulation (tDCS) thereby facilitating re-learning and retaining of normative muscle activation patterns. Methods: This study on 12 healthy volunteers was conducted to investigate the effects of anodal tDCS of the primary motor cortex (M1) and cerebellum on latencies during isometric contraction of tibialis anterior (TA) muscle for myoelectric visual pursuit with quick initiation/termination of muscle activation i.e. ‘ballistic EMG control’ as well as modulation of EMG for ‘proportional EMG control’. Results: The normalized delay in initiation and termination of muscle activity during post-intervention ‘ballistic EMG control’ trials showed a significant main effect of the anodal tDCS target: cerebellar, M1, sham (F(2) = 2.33, p < 0.1), and interaction effect between tDCS target and step-response type: initiation/termination of muscle activation (F(2) = 62.75, p < 0.001), but no significant effect for the step-response type (F(1) = 0.03, p = 0.87). The post-intervention population marginal means during ‘ballistic EMG control’ showed two important findings at 95% confidence interval (critical values from Scheffe’s S procedure): 1. Offline cerebellar anodal tDCS increased the delay in initiation of TA contraction while M1 anodal tDCS decreased the same when compared to sham tDCS, 2. Offline M1 anodal tDCS increased the delay in termination of TA contraction when compared to cerebellar anodal tDCS or sham tDCS. Moreover, online cerebellar anodal tDCS decreased the learning rate during ‘proportional EMG control’ when compared to M1 anodal and sham tDCS. Conclusions: The preliminary results from healthy subjects showed specific, and at least partially antagonistic effects, of M1 and cerebellar anodal tDCS on motor performance during myoelectric control. These results are encouraging, but further studies are necessary to better define how tDCS over particular regions of the cerebellum may facilitate learning of myoelectric control for brain machine interfaces.

Increasing human leg motor cortex excitability by transcranial high frequency random noise stimulation.

Abstract: Purpose: Transcranial random noise stimulation (tRNS) can increase the excitability of hand area of the primary motor cortex (M1). The aim of this study was to compare the efficacy of tRNS and transcranial direct current stimulation (tDCS) on the leg motor cortex. Method: Ten healthy subjects received anodal, cathodal tDCS, tRNS and sham stimulation for 10 min using 2 mA intensity during separate experimental sessions. Single pulse transcranial magnetic stimulation (TMS) induced motor evoked potential (MEP) measurements were used to assess motor cortical excitability changes after the stimulation. Results: Similar to the hand area, we found that both tRNS and anodal tDCS induced an increase of the amplitude of the MEPs. Anodal tDCS induced a constant gradual increase of corticospinal excitability until 60 min post-stimulation, whereas the effect of tRNS was immediate with a duration of 40 min following stimulation. The cathodal tDCS induced decrease in MEP amplitude did not reach statistical significance. Conclusion: Our results suggest that although the leg area has a deeper position in the cortex compared to the hand area, it can be reached by weak transcranial currents. Both anodal tDCS and tRNS had comparable effect on cortical excitability.

Brain-derived neurotrophic factor: its impact upon neuroplasticity and neuroplasticity inducing transcranial brain stimulation protocols

Abstract: Val66Met (rs6265) is a gene variation, a single nucleotide polymorphism (SNP) in the brain-derived neurotrophic factor (BDNF) gene that codes for the protein BDNF. The substitution of Met for Val occurs at position 66 in the pro-region of the BDNF gene and is responsible for altered activity-dependent release and recruitment of BDNF in neurons. This is believed to manifest itself in an altered ability in neuroplasticity induction and an increased predisposition toward a number of neurological disorders. Many studies using neuroplasticity-inducing protocols have investigated the impact of the BDNF polymorphism on cortical modulation and plasticity; however, the results are partly contradictory and dependent on the paradigm used in a given study. The aim of this review is to summarize recent knowledge on the relationship of this BDNF SNP and neuroplasticity.

Do Manual and Voxel-Based Morphometry Measure the Same? A Proof of Concept Study

Abstract: Voxel-based morphometry (VBM) is a commonly used method to study volumetric variations on a whole brain basis. However it is often criticised for potential confounds, mainly based on imperfect spatial registration. We therefore aimed to evaluate if VBM and “gold-standard” manual volumetry are measuring the same effects with respect to subcortical grey matter volumes. Manual regions-of-interest (ROIs) were drawn in the hippocampus, amygdala, nucleus accumbens, thalamus, putamen, pallidum and caudate nucleus bilaterally. Resulting volumes were used for a whole brain VBM correlation analysis with SPM8. The hippocampus, amygdala, putamen and caudate nucleus were correctly identified by SPM using the contemporary high-dimensional normalization (DARTEL toolbox). This strongly suggests that VBM and manual volumetry both are indeed measuring the same effects with regard to subcortical brain structures.

Solving the Orientation Specific Constraints in Transcranial Magnetic Stimulation by Rotating Fields

Abstract: Transcranial Magnetic Stimulation (TMS) is a promising technology for both neurology and psychiatry. Positive treatment outcome has been reported, for instance in double blind, multi-center studies on depression. Nonetheless, the application of TMS towards studying and treating brain disorders is still limited by inter-subject variability and lack of model systems accessible to TMS. The latter are required to obtain a deeper understanding of the biophysical foundations of TMS so that the stimulus protocol can be optimized for maximal brain response, while inter-subject variability hinders precise and reliable delivery of stimuli across subjects. Recent studies showed that both of these limitations are in part due to the angular sensitivity of TMS. Thus, a technique that would eradicate the need for precise angular orientation of the coil would improve both the inter-subject reliability of TMS and its effectiveness in model systems. We show here how rotation of the stimulating field relieves the angular sensitivity of TMS and provides improvements in both issues. Field rotation is attained by superposing the fields of two coils positioned orthogonal to each other and operated with a relative phase shift in time. Rotating field TMS (rfTMS) efficiently stimulates both cultured hippocampal networks and rat motor cortex, two neuronal systems that are notoriously difficult to excite magnetically. This opens the possibility of pharmacological and invasive TMS experiments in these model systems. Application of rfTMS to human subjects overcomes the orientation dependence of standard TMS. Thus, rfTMS yields optimal targeting of brain regions where correct orientation cannot be determined (e.g., via motor feedback) and will enable stimulation in brain regions where a preferred axonal orientation does not exist.

Abstract 18608: Ventricular Myocarditis Coincides With Atrial Myocarditis in Patients

Abstract: Introduction: Studies on the role of inflammatory cells in myocarditis focus mainly on the ventricles. However, little is known about inflammatory cell infiltration of the atria in patients with diagnosed myocarditis. A common complication in myocarditis is atrial fibrillation (AF), which is associated with inflammation of the atria. Therefore, we quantified inflammatory cells both in the ventricles and the atria of patients with lymphocytic myocarditis and catecholamine myocarditis. Methods: From post-mortem obtained hearts of lymphocytic myocarditis patients (n=5), catecholamine myocarditis patients (n=5) and control patients (n=5), tissue slides of the left and right ventricles and left and right atria were stained with antibodies identifying neutrophils, lymphocytes and macrophages. These cells were subsequently quantified in atrial and ventricular myocardium and in the atrial adipose tissue. Results: The number of macrophages were significantly increased in the myocardium of the atria and the ventric...

Transcranial brain stimulation: potential and limitations

Abstract: The brain adapts to new requirements in response to activity, learning or reactions to environmental stimuli by continuous reorganization. These reorganization processes can be facilitated and augmented, or also inhibited and prevented, by transcranial neurostimulation. The most common methods are electrical or magnetic stimulation. However, few studies have dealt with the newer methods using near infrared or ultrasound stimulation. Transcranial magnetic stimulation (TMS) allows the pain-free transfer of very short bursts of high intensity electrical energy through the skull and can induce action potentials. By varying the number and intensity of the stimuli, and the stimulus sequence, repetitive TMS (rTMS) can induce either inhibitory or facilitatory effects in the brain. A differentiation is made between short-lived interference with ongoing brain activity, and plastic changes that persist for a longer period beyond the end of the stimulation. Weaker electric fields in the 1 mA range can be applied painlessly through the skull. These probably exert their effects by modulating neuronal membranes and influencing the spontaneous firing rate of cortical neurons. They encompass the range from transcranial direct current stimulation (tDCS) to high frequency alternating current stimulation (tACS) in the kilohertz range. In view of the multitude of physically possible stimulation algorithms, hypothesis-driven protocols based on cellular or neuronal network characteristics are particularly popular, in the effort to narrow the choices in a meaningful manner. Examples are theta burst stimulation or tACS in the so-called “ripple” frequency range. It is, of course, not possible to selectively stimulate individual neurons using transcranial stimulation techniques; however selective after-effects can be achieved when used in combination with neuropharmacologically active drugs. The use of these methods for neuroenhancement is now a topic of intense discussion.

Low-grade inflammation and endothelial dysfunction explain the association between retinopathy and left ventricular ejection fraction in men: an 8-year follow-up of the Hoorn Study

Abstract: Purpose The aim of this study was to prospectively investigate the association of retinopathy with changes in left ventricular (LV) function. Methods Within the Hoorn Study, a population-based cohort study of diabetes in The Netherlands, retinal photography and echocardiography were performed in the year 2000 (baseline) and 2008 (follow-up). Retinopathy was graded according to the Eurodiab classification and further defined as absent or present retinopathy. LV systolic and diastolic functions were assessed by LV ejection fraction (%), LV mass (g/m 2.7 ) and left atrial (LA) volume indices and the ratio of LV inflow (E) and early diastolic lengthening (e') velocities. Linear regression analyses stratified for sex were completed to investigate associations of retinopathy with changes in LV function in participants with impaired glucose metabolism and type 2 diabetes. Results One hundred forty-seven participants (58% men, mean age 66) were included in the study, of whom 13.6% were present with retinopathy at baseline. LV ejection fraction was similar among participants with and without retinopathy (60.2% versus 60.7%) at baseline. Eight years later, retinopathy was significantly associated with a lower LV ejection fraction (β -8.0 95% CI −15.37 to −0.68) in men, independent of risk factors. Microvascular endothelial dysfunction ([ED] β -4.87 95% CI −13.40 to 3.67) and low-grade inflammation ([LGI] β −5.30 95% CI −13.72 to 3.12) both diminished the association. No significant associations between retinopathy and other LV function parameters were observed. Conclusion Retinopathy was significantly associated with a lower LV ejection fraction in men but not in women. LGI and ED might explain the observed association.

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)

Abstract: 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.