The rationale for repurposing funny current inhibition for management of ventricular arrhythmia

  • Praloy Chakraborty
    The Hull Family Cardiac Fibrillation Management Laboratory, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada

    University Health Network, Toronto, Ontario, Canada
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  • Robert A. Rose
    Libin Cardiovascular Institute of Alberta, An entity of the University of Calgary and Alberta Health Services, Calgary, Alberta, Canada
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  • Krishnakumar Nair
    The Hull Family Cardiac Fibrillation Management Laboratory, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada

    University Health Network, Toronto, Ontario, Canada
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  • Eugene Downar
    The Hull Family Cardiac Fibrillation Management Laboratory, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada

    University Health Network, Toronto, Ontario, Canada
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  • Kumaraswamy Nanthakumar
    Address reprint requests and correspondence: Dr Kumaraswamy Nanthakumar, Division of Cardiology, University Health Network, Toronto General Hospital, 150 Gerrard St West, GW3-526, Toronto, Ontario, Canada M5G 2C4.
    The Hull Family Cardiac Fibrillation Management Laboratory, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada

    University Health Network, Toronto, Ontario, Canada
    Search for articles by this author
      Management of ventricular arrhythmia in structural heart disease is complicated by the toxicity of the limited antiarrhythmic options available. In others, proarrhythmia and deleterious hemodynamic and noncardiac effects prevent practical use. This necessitates new thinking in therapeutic agents for ventricular arrhythmia in structural heart disease. Ivabradine, a funny current (If) inhibitor, has proven safety in heart failure, angina, and inappropriate sinus tachycardia. Although it is commonly known that funny channels are primarily expressed in the sinoatrial node, atrioventricular node, and conducting system of the ventricle, ivabradine is known to exert effects on metabolism, ion homeostasis, and membrane electrophysiology of remodeled ventricular myocardium. This review considers novel concepts and evidence from clinical and experimental studies regarding this paradigm, with a potential role of ivabradine in ventricular arrhythmia.

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        • Alexander J.H.
        • Granger C.B.
        • Sadowski Z.
        • et al.
        Prophylactic lidocaine use in acute myocardial infarction: incidence and outcomes from two international trials. The GUSTO-I and GUSTO-IIb Investigators.
        Am Heart J. 1999; 137: 799-805
        • Uretsky B.F.
        • Sheahan R.G.
        Primary prevention of sudden cardiac death in heart failure: will the solution be shocking?.
        J Am Coll Cardiol. 1997; 30: 1589-1597
        • Saxon L.A.
        • Bristow M.R.
        • Boehmer J.
        • et al.
        Predictors of sudden cardiac death and appropriate shock in the Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) Trial.
        Circulation. 2006; 114: 2766-2772
        • Cleland J.G.
        • Daubert J.C.
        • Erdmann E.
        • et al.
        The effect of cardiac resynchronization on morbidity and mortality in heart failure.
        N Engl J Med. 2005; 352: 1539-1549
        • Tang A.S.
        • Wells G.A.
        • Talajic M.
        • et al.
        Cardiac-resynchronization therapy for mild-to-moderate heart failure.
        N Engl J Med. 2010; 363: 2385-2395
        • Cheng A.
        • Landman S.R.
        • Stadler R.W.
        Reasons for loss of cardiac resynchronization therapy pacing: insights from 32 844 patients.
        Circ Arrhythm Electrophysiol. 2012; 5: 884-888
        • Kuck K.H.
        • Cappato R.
        • Siebels J.
        • Ruppel R.
        Randomized comparison of antiarrhythmic drug therapy with implantable defibrillators in patients resuscitated from cardiac arrest: the Cardiac Arrest Study Hamburg (CASH).
        Circulation. 2000; 102: 748-754
        • Stevenson W.G.
        • Stevenson L.W.
        • Middlekauff H.R.
        • et al.
        Improving survival for patients with atrial fibrillation and advanced heart failure.
        J Am Coll Cardiol. 1996; 28: 1458-1463
        • Flaker G.C.
        • Blackshear J.L.
        • McBride R.
        • Kronmal R.A.
        • Halperin J.L.
        • Hart R.G.
        Antiarrhythmic drug therapy and cardiac mortality in atrial fibrillation. The Stroke Prevention in Atrial Fibrillation Investigators.
        J Am Coll Cardiol. 1992; 20: 527-532
        • Hoffmeister H.M.
        • Hepp A.
        • Seipel L.
        Negative inotropic effect of class-I-antiarrhythmic drugs: comparison of flecainide with disopyramide and quinidine.
        Eur Heart J. 1987; 8: 1126-1132
        • McCauley M.
        • Vallabhajosyula S.
        • Darbar D.
        Proarrhythmic and torsadogenic effects of potassium channel blockers in patients.
        Card Electrophysiol Clin. 2016; 8: 481-493
        • Santangeli P.
        • Muser D.
        • Maeda S.
        • et al.
        Comparative effectiveness of antiarrhythmic drugs and catheter ablation for the prevention of recurrent ventricular tachycardia in patients with implantable cardioverter-defibrillators: a systematic review and meta-analysis of randomized controlled trials.
        Heart Rhythm. 2016; 13: 1552-1559
        • Santangeli P.
        • Di Biase L.
        • Burkhardt J.D.
        • et al.
        Examining the safety of amiodarone.
        Expert Opin Drug Saf. 2012; 11: 191-214
        • Packer D.L.
        • Prutkin J.M.
        • Hellkamp A.S.
        • et al.
        Impact of implantable cardioverter-defibrillator, amiodarone, and placebo on the mode of death in stable patients with heart failure: analysis from the sudden cardiac death in heart failure trial.
        Circulation. 2009; 120: 2170-2176
        • Køber L.
        • Torp-Pedersen C.
        • McMurray J.J.V.
        • et al.
        Increased mortality after dronedarone therapy for severe heart failure.
        N Engl J Med. 2008; 358: 2678-2687
        • Krum H.
        • Ninio D.
        • MacDonald P.
        Baseline predictors of tolerability to carvedilol in patients with chronic heart failure.
        Heart. 2000; 84: 615-619
        • Singh B.N.
        Amiodarone: historical development and pharmacologic profile.
        Am Heart J. 1983; 106: 788-797
        • Swedberg K.
        • Komajda M.
        • Bohm M.
        • et al.
        Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study.
        Lancet. 2010; 376: 875-885
      1. Sartiani L, Cerbai E, Mugelli A. The Funny Current in Cardiac Non-Pacemaker Cells: Functional Role and Pharmacological Modulation. 2011;doi 10.5772/13086.

        • Koncz I.
        • Szel T.
        • Bitay M.
        • et al.
        Electrophysiological effects of ivabradine in dog and human cardiac preparations: potential antiarrhythmic actions.
        Eur J Pharmacol. 2011; 668: 419-426
        • Vaillant F.
        • Lauzier B.
        • Ruiz M.
        • et al.
        Ivabradine and metoprolol differentially affect cardiac glucose metabolism despite similar heart rate reduction in a mouse model of dyslipidemia.
        Am J Physiol Heart Circ Physiol. 2016; 311: H991-H1003
        • Rushworth G.F.
        • Lambrakis P.
        • Leslie S.J.
        Ivabradine: a new rate-limiting therapy for coronary artery disease and heart failure.
        Ther Adv Drug Saf. 2011; 2: 19-28
        • DiFrancesco D.
        The contribution of the 'pacemaker' current (If) to generation of spontaneous activity in rabbit sino-atrial node myocytes.
        J Physiol. 1991; 434: 23-40
        • Wahl-Schott C.
        • Biel M.
        HCN channels: structure, cellular regulation and physiological function.
        Cell Mol Life Sci. 2009; 66: 470-494
        • Michels G.
        • Brandt M.C.
        • Zagidullin N.
        • et al.
        Direct evidence for calcium conductance of hyperpolarization-activated cyclic nucleotide-gated channels and human native If at physiological calcium concentrations.
        Cardiovasc Res. 2008; 78: 466-475
        • DiFrancesco D.
        • Tortora P.
        Direct activation of cardiac pacemaker channels by intracellular cyclic AMP.
        Nature. 1991; 351: 145-147
        • Biel M.
        • Wahl-Schott C.
        • Michalakis S.
        • Zong X.
        Hyperpolarization-activated cation channels: from genes to function.
        Physiol Rev. 2009; 89: 847-885
        • Roubille F.
        • Tardif J.C.
        New therapeutic targets in cardiology: heart failure and arrhythmia: HCN channels.
        Circulation. 2013; 127: 1986-1996
        • Psotka M.A.
        • Teerlink J.R.
        Ivabradine: role in the chronic heart failure armamentarium.
        Circulation. 2016; 133: 2066-2075
        • Mackiewicz U.
        • Gerges J.Y.
        • Chu S.
        • et al.
        Ivabradine protects against ventricular arrhythmias in acute myocardial infarction in the rat.
        J Cell Physiol. 2014; 229: 813-823
        • Bigger Jr., J.T.
        Why patients with congestive heart failure die: arrhythmias and sudden cardiac death.
        Circulation. 1987; 75: Iv28-35
        • Patel J.
        • Heywood J.T.
        Mode of death in patients with systolic heart failure.
        J Cardiovasc Pharmacol Ther. 2007; 12: 127-136
        • Bohm M.
        • Swedberg K.
        • Komajda M.
        • et al.
        Heart rate as a risk factor in chronic heart failure (SHIFT): the association between heart rate and outcomes in a randomised placebo-controlled trial.
        Lancet. 2010; 376: 886-894
        • Kuwabara Y.
        • Kuwahara K.
        • Takano M.
        • et al.
        Increased expression of HCN channels in the ventricular myocardium contributes to enhanced arrhythmicity in mouse failing hearts.
        J Am Heart Assoc. 2013; 2e000150
        • Mughal L.H.
        • Houghton A.R.
        • Khoo J.
        Significant suppression of premature ventricular ectopics with ivabradine in dilated cardiomyopathy.
        Br J Cardiol. 2019; 26: 36-37
        • Vaksmann G.
        • Klug D.
        Efficacy of ivabradine to control ventricular arrhythmias in catecholaminergic polymorphic ventricular tachycardia.
        Pacing Clin Electrophysiol. 2018; 41: 1378-1380
        • Frommeyer G.
        • Weller J.
        • Ellermann C.
        • et al.
        Ivabradine reduces digitalis-induced ventricular arrhythmias.
        Basic Clin Pharmacol Toxicol. 2017; 121: 526-530
        • Milliez P.
        • Messaoudi S.
        • Nehme J.
        • Rodriguez C.
        • Samuel J.L.
        • Delcayre C.
        Beneficial effects of delayed ivabradine treatment on cardiac anatomical and electrical remodeling in rat severe chronic heart failure.
        Am J Physiol Heart Circ Physiol. 2009; 296: H435-H441
        • Yang K.-C.
        • Kyle J.W.
        • Makielski J.C.
        • Dudley Jr., S.C.
        Mechanisms of sudden cardiac death: oxidants and metabolism.
        Circ Res. 2015; 116: 1937-1955
        • Barth Andreas S.
        • Tomaselli Gordon F.
        Cardiac metabolism and arrhythmias.
        Circ Arrhythm Electrophysiol. 2009; 2: 327-335
        • Grisanti L.A.
        Diabetes and arrhythmias: pathophysiology, mechanisms and therapeutic outcomes.
        Front Physiol. 2018; 9 (1669–1669)
        • Jaffe A.S.
        • Spadaro J.J.
        • Schechtman K.
        • Roberts R.
        • Geltman E.M.
        • Sobel B.E.
        Increased congestive heart failure after myocardial infarction of modest extent in patients with diabetes mellitus.
        Am Heart J. 1984; 108: 31-37
        • Lunde I.G.
        • Aronsen J.M.
        • Kvaloy H.
        • et al.
        Cardiac O-GlcNAc signaling is increased in hypertrophy and heart failure.
        Physiol Genomics. 2012; 44: 162-172
        • Wende A.R.
        Post-translational modifications of the cardiac proteome in diabetes and heart failure.
        Proteomics Clin Appl. 2016; 10: 25-38
        • Erickson J.R.
        • Pereira L.
        • Wang L.
        • et al.
        Diabetic hyperglycaemia activates CaMKII and arrhythmias by O-linked glycosylation.
        Nature. 2013; 502: 372-376
        • McLarty J.L.
        • Marsh S.A.
        • Chatham J.C.
        Post-translational protein modification by O-linked N-acetyl-glucosamine: its role in mediating the adverse effects of diabetes on the heart.
        Life Sci. 2013; 92: 621-627
        • Yokoe S.
        • Asahi M.
        • Takeda T.
        • et al.
        Inhibition of phospholamban phosphorylation by O-GlcNAcylation: implications for diabetic cardiomyopathy.
        Glycobiology. 2010; 20: 1217-1226
        • Lauzier B.
        • Vaillant F.
        • Gélinas R.
        • et al.
        Ivabradine reduces heart rate while preserving metabolic fluxes and energy status of healthy normoxic working hearts.
        Am J Physiol Heart Circ Physiol. 2011; 300: H845-H852
        • Sartiani L.
        • Bettiol E.
        • Stillitano F.
        • Mugelli A.
        • Cerbai E.
        • Jaconi M.E.
        Developmental changes in cardiomyocytes differentiated from human embryonic stem cells: a molecular and electrophysiological approach.
        Stem Cells. 2007; 25: 1136-1144
        • Yasui K.
        • Liu W.
        • Opthof T.
        • et al.
        If current and spontaneous activity in mouse embryonic ventricular myocytes.
        Circ Res. 2001; 88: 536-542
        • Fenske S.
        • Mader R.
        • Scharr A.
        • et al.
        HCN3 contributes to the ventricular action potential waveform in the murine heart.
        Circ Res. 2011; 109: 1015-1023
        • Sartiani L.
        • Stillitano F.
        • Cerbai E.
        • Mugelli A.
        Electrophysiologic changes in heart failure: focus on pacemaker channels.
        Can J Physiol Pharmacol. 2009; 87: 84-90
        • Munier M.
        • Law F.
        • Meduri G.
        • Le Menuet D.
        • Lombès M.
        Mineralocorticoid receptor overexpression facilitates differentiation and promotes survival of embryonic stem cell-derived neurons.
        Endocrinology. 2012; 153: 1330-1340
        • Cerbai E.
        • Barbieri M.
        • Mugelli A.
        Occurrence and properties of the hyperpolarization-activated current If in ventricular myocytes from normotensive and hypertensive rats during aging.
        Circulation. 1996; 94: 1674-1681
        • Cerbai E.
        • Sartiani L.
        • DePaoli P.
        • et al.
        The properties of the pacemaker current If in human ventricular myocytes are modulated by cardiac disease.
        J Mol Cell Cardiol. 2001; 33: 441-448
        • Stillitano F.
        • Lonardo G.
        • Zicha S.
        • et al.
        Molecular basis of funny current (If) in normal and failing human heart.
        J Mol Cell Cardiol. 2008; 45: 289-299
        • Barbieri M.
        • Varani K.
        • Cerbai E.
        • et al.
        Electrophysiological basis for the enhanced cardiac arrhythmogenic effect of isoprenaline in aged spontaneously hypertensive rats.
        J Mol Cell Cardiol. 1994; 26: 849-860
        • Cerbai E.
        • Mugelli A.
        If in non-pacemaker cells: role and pharmacological implications.
        Pharmacol Res. 2006; 53: 416-423
        • Brack K.E.
        • Winter J.
        • Ng G.A.
        Mechanisms underlying the autonomic modulation of ventricular fibrillation initiation—tentative prophylactic properties of vagus nerve stimulation on malignant arrhythmias in heart failure.
        Heart Fail Rev. 2013; 18: 389-408
        • Suffredini S.
        • Stillitano F.
        • Comini L.
        • et al.
        Long-term treatment with ivabradine in post-myocardial infarcted rats counteracts f-channel overexpression.
        Br J Pharmacol. 2012; 165: 1457-1466
        • Haechl N.
        • Ebner J.
        • Hilber K.
        • Todt H.
        • Koenig X.
        Pharmacological profile of the bradycardic agent ivabradine on human cardiac ion channels.
        Cell Physiol Biochem. 2019; 53: 36-48
        • Melgari D.
        • Brack K.E.
        • Zhang C.
        • et al.
        hERG potassium channel blockade by the HCN channel inhibitor bradycardic agent ivabradine.
        J Am Heart Assoc. 2015; 4e001813
        • Camm A.J.
        • Lau C.P.
        Electrophysiological effects of a single intravenous administration of ivabradine (S 16257) in adult patients with normal baseline electrophysiology.
        Drugs R D. 2003; 4: 83-89
        • Costard-Jäckle A.
        • Franz M.R.
        Frequency-dependent antiarrhythmic drug effects on postrepolarization refractoriness and ventricular conduction time in canine ventricular myocardium in vivo.
        J Pharmacol Exp Ther. 1989; 251: 39-46
        • Hofmann F.
        • Fabritz L.
        • Stieber J.
        • et al.
        Ventricular HCN channels decrease the repolarization reserve in the hypertrophic heart.
        Cardiovasc Res. 2012; 95: 317-326
        • Michael G.
        • Xiao L.
        • Qi X.Y.
        • Dobrev D.
        • Nattel S.
        Remodelling of cardiac repolarization: how homeostatic responses can lead to arrhythmogenesis.
        Cardiovasc Res. 2009; 81: 491-499
        • Fernández-Velasco M.
        • Goren N.
        • Benito G.
        • Blanco-Rivero J.
        • Boscá L.
        • Delgado C.
        Regional distribution of hyperpolarization-activated current (If) and hyperpolarization-activated cyclic nucleotide-gated channel mRNA expression in ventricular cells from control and hypertrophied rat hearts.
        J Physiol. 2003; 553: 395-405
        • Sartiani L.
        • De Paoli P.
        • Stillitano F.
        • et al.
        Functional remodeling in post-myocardial infarcted rats: focus on beta-adrenoceptor subtypes.
        J Mol Cell Cardiol. 2006; 40: 258-266
        • Fenske S.
        • Krause S.
        • Biel M.
        • Wahl-Schott C.
        The role of HCN channels in ventricular repolarization.
        Trends Cardiovasc Med. 2011; 21: 216-220
        • Nattel S.
        • Maguy A.
        • Le Bouter S.
        • Yeh Y.H.
        Arrhythmogenic ion-channel remodeling in the heart: heart failure, myocardial infarction, and atrial fibrillation.
        Physiol Rev. 2007; 87: 425-456
        • Ceconi C.
        • Comini L.
        • Suffredini S.
        • et al.
        Heart rate reduction with ivabradine prevents the global phenotype of left ventricular remodeling.
        Am J Physiol Heart Circ Physiol. 2011; 300: H366-H373
        • Savelieva I.
        • Camm A.J.
        Novel If current inhibitor ivabradine: safety considerations.
        Adv Cardiol. 2006; 43: 79-96