J Physiol 592.3 (2014) pp 421–422 421

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Rebuttal from Zoltan Papp, AttilaBorbely and Walter J. Paulus

Zoltan Papp1, Attila Borbely1

and Walter J. Paulus2

1Division of Clinical Physiology, ResearchCenter for Molecular Medicine, Institute ofCardiology, Faculty of Medicine, Medicaland Health Science Center, University ofDebrecen, Debrecen, Hungary2Department of Physiology, Institutefor Cardiovascular Research VU, VUUniversity Medical Center Amsterdam,Amsterdam, The Netherlands

Email: pappz@med.unideb.hu

In their article Pourrier et al. (2014) pre-sented supportive information for the roleof INa,late (INa,L) in the pathogenesis ofHFpEF, and concluded that: (1) INa,L isincreased in many pathological conditions,(2) INa,L is an important contributor todiastolic dysfunction in HFpEF. While weperfectly agree with the first conclusionwe have reservations about the second.Indeed, these days there is little doubt aboutthe pathological increase in INa,L and thedysregulation of [Ca2+]i homeostasis inthe failing heart. However, the proof for amechanistic relationship between increasedINa,L and diastolic dysfunction requiresfurther evidence for HFpEF, in particularin humans.

Of note, one finds differentepidemiological and phenotypicalcharacteristics for HFpEF and HFrEF(heart rate with reduced ejection fraction;Mohammed et al. 2012). In our view,species-dependent characteristics arefurther complicated by the choice ofexperimental models where separationbetween systolic heart failure and diastolicheart failure (i.e. HFpEF vs. HFrEF) arerarely made. Therefore, it appears to beimportant to stress again that in HFpEFthe signs and symptoms of heart failuredevelop despite an apparently normal(or near normal) LV systolic function. Incontrast, most preclinical data for INa,L havebeen derived from studies where systolicventricular dysfunction (with reducedejection fraction and ischaemic cardio-myopathy) was clearly present (Sabbah etal. 2002; Maltsev et al. 2007; Sossalla et al.2008). Hence, future model studies should

try to avoid overlaps between HFpEF andHFrEF.

We anticipated that our opponent also feltcritical about the specificity of ranolazine,and appreciate his efforts in findingsupportive evidence with alternative INa,L

inhibitors (i.e. terodotoxin and GS967;Qian et al. 2012; Belardinelli et al.2013). We also acknowledge the strengthof those experimental data where thefrequency-dependent increase in [Ca2+]i

was demonstrated in human cardio-myocytes isolated from patients with hyper-trophic cardiomyopathy (Coppini et al.2013). We strongly believe that futurestudies in human isolated cardiomyocytepreparations from HFpEF patients with INa,L

antagonists other than ranolazine will shednew light on the pathophysiology of HFpEF.

Finally, we would like to underlinethat current data on the clinical useof INa,L inhibitors suffer from the sameconceptual problems as those in preclinicalstudies (i.e. confusion of HFpEF withHFrEF and the aspecificity of ranolazine;Hayashida et al. 1994; Figueredo et al.2011). Hence, for the evaluation of theclinical significance of INa,L further studiesare clearly warranted where clinical,epidemiological and pharmacologicaldata should be carefully taken intoconsideration.

Call for comments

Readers are invited to give their views on thisand the accompanying CrossTalk articles in thisissue by submitting a brief comment. Commentsmay be posted up to 6 weeks after publicationof the article, at which point the discussionwill close and authors will be invited to submita ‘final word’. To submit a comment, go tohttp://jp.physoc.org/letters/submit/jphysiol;592/3/421

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C© 2013 The Authors. The Journal of Physiology C© 2013 The Physiological Society DOI: 10.1113/jphysiol.2013.268904

422 CrossTalk J Physiol 592.3

Additional information

Competing interests

None declared.

Funding

Supported by grants from theEuropean Commission (FP7-Health-2010;MEDIA-261409), by the Social RenewalOperational Programme (TAMOP-4.2.2.A-11/1/KONV-2012–0045) and by Hungarian Scientific

Research Fund (OTKA K 109083 and OTKAPD 108614) and co-financed by the EuropeanSocial Fund in the framework of TAMOP4.2.4. A/2–11–1–2012–0001 ‘National ExcellenceProgram’.

C© 2013 The Authors. The Journal of Physiology C© 2013 The Physiological Society