Inhibition of Funny current (If) leading to Arrhythmias

Sun-Woong Kang^a, Myeong Hwa Song^b  ,Do-Sun Lim ^b and Kim Young Jun^c 

^aCenter for Biomimetic Research, Korea Institute of Toxicology, Daejeon 34114, Korea

^bCardiovascular Center, Department of Cardiology, Korea University Anam Hospital, Korea University College of Medicine, Seoul, South Korea

^cEnvironemental Safety Group, KIST Europe, campus E 71 Saarbruecken, Germany 

Inhibition of If channels, responsible for the funny current (If) in sinoatrial (SA) node pacemaker cells, can lead to arrhythmias by disrupting normal cardiac electrical activity. If channels regulate spontaneous depolarization during Phase 4 of the cardiac action potential and control heart rate through autonomic modulation. While If channel inhibitors, such as ivabradine, are effective in reducing heart rate in conditions like chronic heart failure or inappropriate sinus tachycardia, excessive inhibition can result in sinus node suppression and conduction abnormalities. Associated arrhythmias include sinus bradycardia, sinus pauses, atrioventricular (AV) block, and junctional escape rhythms. Bradycardia induced by If inhibition can promote ectopic activity, increasing the risk of atrial fibrillation, atrial flutter, and ventricular ectopy. Additionally, slower heart rates may facilitate early or delayed afterdepolarizations (EADs or DADs), creating conditions for reentrant arrhythmias. Genetic mutations in HCN4, the gene encoding If channels, further highlight the link between If dysfunction and arrhythmogenesis, including sinus node dysfunction and atrial fibrillation. While If channel inhibitors offer therapeutic benefits, their potential to induce or exacerbate arrhythmias necessitates careful monitoring and individualized application to minimize adverse cardiac effects.

This Adverse Outcome Pathway (AOP) describes the mechanistic progression from the inhibition of the Funny Current (If)—a key pacemaker current responsible for regulating the heart's rhythmic activity—to the development of arrhythmias. The Funny Current, primarily mediated by hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, plays a critical role in controlling heart rate and stabilizing cardiac rhythm. Its inhibition disrupts pacemaker activity in the sinoatrial (SA) node, leading to electrical instability and arrhythmias.

Problem Formulation

Objective

To outline the mechanistic progression from the inhibition of the Funny Current (If) in pacemaker cells to the adverse outcome of cardiac arrhythmias.

To identify key events (KEs), key event relationships (KERs), and modulating factors affecting the progression.

Relevance

The If current, mediated by HCN channels, is essential for regulating pacemaker activity in the sinoatrial (SA) node. Its inhibition by drugs (e.g., ivabradine), genetic mutations, or toxins can cause bradycardia and arrhythmias.

This AOP is relevant to drug safety assessments and regulatory toxicology.

Identification of Key Events (KEs)

The AOP is structured into a sequence of measurable biological changes leading from the molecular initiating event (MIE) to the adverse outcome (AO).

MIE: Inhibition of Funny Current (If)

Inhibition of HCN channels reduces the depolarizing current in pacemaker cells.

KE1: Slowed Heart Rate (Bradycardia)

Reduced pacemaker activity manifests as a slower heart rate.

KE2: Altered Cardiac Electrical Conduction

Bradycardia disrupts the timing and synchronization of electrical signals across the heart, leading to conduction delays or blocks.

AO: Arrhythmias

Electrical instability culminates in irregular heart rhythms, including sinus pauses, AV blocks, or ventricular tachyarrhythmias.

Evidence Collection and Screening

Data Sources

In Vitro Studies:

Electrophysiological recordings of If currents in isolated pacemaker cells.

In Vivo Studies:

Animal models treated with If inhibitors or carrying HCN mutations.

Clinical Data:

ECG-based studies in patients treated with drugs like ivabradine.

Computational Models:

Simulations of pacemaker activity and cardiac conduction under varying levels of If inhibition.

Screening Criteria

Relevance: Data must directly address KEs or KERs in the pathway.

Quality: Prioritize peer-reviewed studies with robust methodologies.

Consistency: Focus on findings that align with the proposed sequence of events.

Validation and Refinement

Validate the AOP using experimental, computational, and clinical data.

Refine quantitative relationships and identify additional modulators based on emerging evidence.

The Adverse Outcome Pathway (AOP): Inhibition of Funny Current (If) Leading to Arrhythmias provides a mechanistic framework linking the inhibition of the Funny Current (If), a critical pacemaker current mediated by hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, to the adverse outcome of cardiac arrhythmias. The inhibition of If disrupts the diastolic depolarization of sinoatrial (SA) node pacemaker cells, leading to reduced pacemaker activity and bradycardia. This cascade of events progresses to altered cardiac conduction, characterized by conduction delays or blocks, and ultimately results in arrhythmias, such as sinus pauses, atrioventricular (AV) blocks, or ventricular tachyarrhythmias.

This AOP has strong biological plausibility, supported by evidence from molecular, cellular, in vivo, and clinical studies. Key stressors include pharmacological agents such as ivabradine, a selective If inhibitor, as well as genetic mutations in HCN4 and potential environmental toxins. Empirical evidence demonstrates consistent dose-response relationships between If inhibition and bradycardia, as well as temporal concordance between intermediate key events and adverse outcomes. Quantitative understanding of early events, such as the inhibition of HCN channels and reduction in pacemaker activity, is well-established, though further refinement is needed for later events like conduction disruption and arrhythmias.

This AOP has diverse applications across regulatory toxicology, drug safety evaluation, therapeutic development, and environmental risk assessment. In regulatory contexts, it can be used to identify and prioritize chemicals or drugs that inhibit If and pose arrhythmogenic risks. High-throughput screening platforms (e.g., ToxCast, Tox21) can assess the cardiotoxic potential of compounds, while read-across approaches allow predictions based on data from structurally or mechanistically similar substances. In drug safety evaluation, the AOP can guide preclinical and clinical testing of HCN-targeting drugs or those with off-target If inhibition. It also supports therapeutic development by identifying safer HCN modulators and optimizing dosing regimens to minimize adverse cardiac effects. Personalized medicine applications include genetic screening for HCN4 mutations and precision dosing strategies for individuals at heightened risk of arrhythmias.

The AOP framework also facilitates environmental risk assessments by evaluating the impact of If inhibition in both human populations and non-human species, particularly in ecosystems where cardiac function is disrupted by environmental stressors. Additionally, it enables the development of in silico and in vitro models to predict arrhythmogenic potential efficiently and cost-effectively. Despite its robust foundation, addressing data gaps, such as thresholds for arrhythmias and species-specific differences, will enhance its predictive utility. This AOP is a valuable tool for advancing safety assessments and therapeutic innovations while mitigating the risks of cardiac arrhythmias associated with If inhibition.

DiFrancesco D. The role of the funny current in pacemaker activity. Circulation Research. 2010;106(3):434–446.

Baruscotti M, Bucchi A, Difrancesco D. Physiology and pharmacology of the cardiac pacemaker ("funny") current. Pharmacology & Therapeutics. 2005;107(1):59–79.

Bucchi A, Baruscotti M, Difrancesco D. Current-dependent block of rabbit sino-atrial node I(f) channels by ivabradine. The Journal of General Physiology. 2002;120(1):1–13.

Herrmann S, Stieber J, Stöckl G, et al. HCN4 channel mutations cause autosomal dominant sinus node dysfunction and atrial fibrillation. Nature Genetics. 2007;39(6):766–768.

Stieber J, Stockl G, Herrmann S, et al. Functional expression of the human HCN4 channel and its regulation by cyclic AMP. The Journal of Biological Chemistry. 2004;279(14):14071–14079.

Monfredi O, Dobrzynski H, Mondal T, et al. The anatomy and physiology of the sinoatrial node—a contemporary review. Pacing and Clinical Electrophysiology. 2010;33(11):1392–1406.

Thollon C, Cambarrat C, Vian J, et al. Electrophysiological effects of S 16257, a novel sinoatrial node I(f) current inhibitor, on rabbit and guinea pig cardiac preparations: Comparison with UL-FS 49. European Journal of Pharmacology. 1994;260(1):85–92.

Zaza A, DiFrancesco D. Control of cardiac rate by "funny" channels in health and disease. Annals of the New York Academy of Sciences. 2005;1047:193–199.

Bucchi A, Baruscotti M, Nardini M, et al. I(f)-dependent modulation of pacemaker rate mediated by cAMP in the presence of ivabradine. Journal of Molecular and Cellular Cardiology. 2007;42(3):578–586.

Verkerk AO, van Borren MMGJ, Peters RJG, et al. Pacemaker current (If) in the human sinoatrial node. European Heart Journal. 2007;28(20):2472–2478.

DiFrancesco D, Tortora P. Direct activation of cardiac pacemaker channels by intracellular cyclic AMP. Nature. 1991;351(6322):145–147.

Accili EA, Proenza C, Baruscotti M, DiFrancesco D. From funny current to HCN channels: 20 years of excitation. News in Physiological Sciences. 2002;17:32–37.

Verkerk AO, Wilders R, van Borren MMGJ, et al. Pacemaker activity of the human sinoatrial node: Role of the hyperpolarization-activated current, If. International Journal of Cardiology. 2009;132(3):383–392.

Bucchi A, Baruscotti M, Nardini M, et al. Heart rate reduction via selective ‘funny’ channel blockers. Current Opinion in Pharmacology. 2007;7(2):208–213

Stillitano F, Lonardo G, Zicha S, et al. Molecular basis of funny current (If) in normal and failing human heart. The Journal of Molecular and Cellular Cardiology. 2008;45(2):289–299.

Postea O, Biel M. Exploring HCN channels as drug targets. Nature Reviews Drug Discovery. 2011;10(12):903–914.

Mesirca P, Marger L, Torrente AG, et al. The funny current and cardiac rhythm: Insights from HCN knockout and transgenic mouse models. Frontiers in Physiology. 2015;6:46.

Wahl-Schott C, Biel M. HCN channels: Structure, cellular regulation, and physiological function. Physiological Reviews. 2009;89(3):847–885.

Nof E, Luria D, Brass D, et al. Point mutation in the HCN4 gene causes a mild form of inappropriate sinus tachycardia. Journal of the American College of Cardiology. 2007;50(9):807–813.

Baruscotti M, Bucchi A, Viscomi C, et al. Deep bradycardia and heart block caused by inducible cardiac-specific knockout of the pacemaker channel gene Hcn4. Proceedings of the National Academy of Sciences. 2011;108(4):1705–1710.