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      Differential regulation of sodium channels as a novel proarrhythmic mechanism in the human failing heart

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          Abstract

          <p class="first" id="d4940343e247">In heart failure (HF), enhanced persistent Na+ current (INaL) exerts detrimental effects on cellular electrophysiology and can induce arrhythmias. However, the underlying regulatory mechanisms remain unclear. Our aim was to potentially investigate the regulation and electrophysiological contribution of neuronal sodium channel NaV1.8 in failing human heart and eventually to reveal a novel anti-arrhythmic therapy. </p>

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          The tetrodotoxin-resistant sodium channel SNS has a specialized function in pain pathways.

          L Stanfa, N Ogata, S. J. McMahon … (1999)
          Many damage-sensing neurons express tetrodotoxin (TTX)-resistant voltage-gated sodium channels. Here we examined the role of the sensory-neuron-specific (SNS) TTX-resistant sodium channel alpha subunit in nociception and pain by constructing sns-null mutant mice. These mice expressed only TTX-sensitive sodium currents on step depolarizations from normal resting potentials, showing that all slow TTX-resistant currents are encoded by the sns gene. Null mutants were viable, fertile and apparently normal, although lowered thresholds of electrical activation of C-fibers and increased current densities of TTX-sensitive channels demonstrated compensatory upregulation of TTX-sensitive currents in sensory neurons. Behavioral studies demonstrated a pronounced analgesia to noxious mechanical stimuli, small deficits in noxious thermoreception and delayed development of inflammatory hyperalgesia. These data show that SNS is involved in pain pathways and suggest that blockade of SNS expression or function may produce analgesia without side effects.
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            Genome-wide association study of PR interval

            Arne Pfeufer, Charlotte van Noord, Kristin Marciante … (2010)
            The electrocardiographic PR interval reflects atrial and atrioventricular nodal conduction, disturbances of which increase risk of atrial fibrillation (AF). To identify underlying common genetic variation, we meta-analyzed genome-wide association results for PR interval from seven community-based studies of European-ancestry individuals in the CHARGE consortium: AGES, ARIC, CHS, FHS, KORA, Rotterdam Study, and SardiNIA (N=28,517). Statistically significant loci (P<5×10-8) were tested for association with AF (N=5,741 cases). We identified nine loci associated with PR interval. At chromosome 3p22.2, we observed two independent associations in voltage gated sodium channel genes SCN10A and SCN5A, while six loci were near cardiac developmental genes CAV1/CAV2, NKX2-5 (CSX1), SOX5, WNT11, MEIS1, and TBX5/TBX3. Another signal was at ARHGAP24, a locus without known relevance to the heart. Five of the nine loci, SCN5A, SCN10A, NKX2-5, CAV1/CAV2, and SOX5, were also associated with AF (P<0.0056). Common genetic variation, particularly in ion channel and developmental genes, contributes significantly to atrial and atrioventricular conduction and to AF risk.
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              Ca2+/calmodulin-dependent protein kinase II regulates cardiac Na+ channels.

              Joan Heller Brown, Paulus Kirchhof, Ilko L. Maier … (2006)
              In heart failure (HF), Ca(2+)/calmodulin kinase II (CaMKII) expression is increased. Altered Na(+) channel gating is linked to and may promote ventricular tachyarrhythmias (VTs) in HF. Calmodulin regulates Na(+) channel gating, in part perhaps via CaMKII. We investigated effects of adenovirus-mediated (acute) and Tg (chronic) overexpression of cytosolic CaMKIIdelta(C) on Na(+) current (I(Na)) in rabbit and mouse ventricular myocytes, respectively (in whole-cell patch clamp). Both acute and chronic CaMKIIdelta(C) overexpression shifted voltage dependence of Na(+) channel availability by -6 mV (P < 0.05), and the shift was Ca(2+) dependent. CaMKII also enhanced intermediate inactivation and slowed recovery from inactivation (prevented by CaMKII inhibitors autocamtide 2-related inhibitory peptide [AIP] or KN93). CaMKIIdelta(C) markedly increased persistent (late) inward I(Na) and intracellular Na(+) concentration (as measured by the Na(+) indicator sodium-binding benzofuran isophthalate [SBFI]), which was prevented by CaMKII inhibition in the case of acute CaMKIIdelta(C) overexpression. CaMKII coimmunoprecipitates with and phosphorylates Na(+) channels. In vivo, transgenic CaMKIIdelta(C) overexpression prolonged QRS duration and repolarization (QT intervals), decreased effective refractory periods, and increased the propensity to develop VT. We conclude that CaMKII associates with and phosphorylates cardiac Na(+) channels. This alters I(Na) gating to reduce availability at high heart rate, while enhancing late I(Na) (which could prolong action potential duration). In mice, enhanced CaMKIIdelta(C) activity predisposed to VT. Thus, CaMKII-dependent regulation of Na(+) channel function may contribute to arrhythmogenesis in HF.
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                Author and article information

                Journal
                Title: Cardiovascular Research
                Publisher: Oxford University Press (OUP)
                ISSN (Print): 0008-6363
                ISSN (Electronic): 1755-3245
                Publication date Created: November 01 2018
                Publication date Created: November 01 2018
                Publication date Created: June 20 2018
                Publication date Other: November 01 2018
                Publication date (Print): November 01 2018
                Publication date (Electronic): June 20 2018
                Volume: 114
                Issue: 13
                Pages: 1728-1737
                Affiliations
                [1 ]Clinic for Cardiology & Pneumology, Georg-August University Goettingen, DZHK (German Centre for Cardiovascular Research), partner site Goettingen, Germany
                [2 ]Department of Internal Medicine II, University Medical Center Regensburg, Germany
                [3 ]Department of Thoracic, Cardiac and Vascular Surgery, Georg-August University Goettingen, Germany
                [4 ]Department of Cardiology, Medical University of Graz, Austria
                [5 ]Department of Thoracic, Cardiac and Vascular Surgery (Heart and Diabetes Center), North Rhine Westphalia, Bad Oeynhausen, Germany
                [6 ]Department of Medical Statistics, University Medical Center Goettingen, Germany
                [7 ]Department of Internal Medicine III, Molecular Cardiology and Angiology, University Medical Center, Campus Kiel, Schleswig-Holstein, Germany
                Article
                DOI: 10.1093/cvr/cvy152
                PubMed ID: 29931291
                SO-VID: 77878b92-2b4a-4155-b9f1-257b19cb9ab4
                Copyright © © 2018
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                https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model

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