Rebuttal from Zoltán Papp, Attila Borbély and Walter J. Paulus

Authors

  • Zoltán Papp,

    Corresponding author
    1. Division of Clinical Physiology, Research Center for Molecular Medicine, Institute of Cardiology, Faculty of Medicine, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary
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  • Attila Borbély,

    1. Division of Clinical Physiology, Research Center for Molecular Medicine, Institute of Cardiology, Faculty of Medicine, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary
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  • Walter J. Paulus

    1. Department of Physiology, Institute for Cardiovascular Research VU, VU University Medical Center Amsterdam, Amsterdam, The Netherlands
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In their article Pourrier et al. (2014) presented supportive information for the role of INa,late (INa,L) in the pathogenesis of HFpEF, and concluded that: (1) INa,L is increased in many pathological conditions, (2) INa,L is an important contributor to diastolic dysfunction in HFpEF. While we perfectly agree with the first conclusion we have reservations about the second. Indeed, these days there is little doubt about the pathological increase in INa,L and the dysregulation of [Ca2+]i homeostasis in the failing heart. However, the proof for a mechanistic relationship between increased INa,L and diastolic dysfunction requires further evidence for HFpEF, in particular in humans.

Of note, one finds different epidemiological and phenotypical characteristics for HFpEF and HFrEF (heart rate with reduced ejection fraction; Mohammed et al. 2012). In our view, species-dependent characteristics are further complicated by the choice of experimental models where separation between systolic heart failure and diastolic heart failure (i.e. HFpEF vs. HFrEF) are rarely made. Therefore, it appears to be important to stress again that in HFpEF the signs and symptoms of heart failure develop despite an apparently normal (or near normal) LV systolic function. In contrast, most preclinical data for INa,L have been derived from studies where systolic ventricular dysfunction (with reduced ejection fraction and ischaemic cardiomyopathy) was clearly present (Sabbah et al. 2002; Maltsev et al. 2007; Sossalla et al. 2008). Hence, future model studies should try to avoid overlaps between HFpEF and HFrEF.

We anticipated that our opponent also felt critical about the specificity of ranolazine, and appreciate his efforts in finding supportive evidence with alternative INa,L inhibitors (i.e. terodotoxin and GS967; Qian et al. 2012; Belardinelli et al. 2013). We also acknowledge the strength of those experimental data where the frequency-dependent increase in [Ca2+]i was demonstrated in human cardiomyocytes isolated from patients with hypertrophic cardiomyopathy (Coppini et al. 2013). We strongly believe that future studies in human isolated cardiomyocyte preparations from HFpEF patients with INa,L antagonists other than ranolazine will shed new light on the pathophysiology of HFpEF.

Finally, we would like to underline that current data on the clinical use of INa,L inhibitors suffer from the same conceptual problems as those in preclinical studies (i.e. confusion of HFpEF with HFrEF and the aspecificity of ranolazine; Hayashida et al. 1994; Figueredo et al. 2011). Hence, for the evaluation of the clinical significance of INa,L further studies are clearly warranted where clinical, epidemiological and pharmacological data should be carefully taken into consideration.

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Additional information

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’.

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