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AOP: 562

Title

A descriptive phrase which references both the Molecular Initiating Event and Adverse Outcome.It should take the form “MIE leading to AO”. For example, “Aromatase inhibition leading to reproductive dysfunction” where Aromatase inhibition is the MIE and reproductive dysfunction the AO. In cases where the MIE is unknown or undefined, the earliest known KE in the chain (i.e., furthest upstream) should be used in lieu of the MIE and it should be made clear that the stated event is a KE and not the MIE.  More help

HCN Channel Inhibition leading to Arrhythmias

Short name
A name that succinctly summarises the information from the title. This name should not exceed 90 characters. More help
hyperpolarization-activated cyclic nucleotide-gated (HCN) channels
The current version of the Developer's Handbook will be automatically populated into the Handbook Version field when a new AOP page is created.Authors have the option to switch to a newer (but not older) Handbook version any time thereafter. More help
Handbook Version v2.7

Graphical Representation

A graphical representation of the AOP.This graphic should list all KEs in sequence, including the MIE (if known) and AO, and the pair-wise relationships (links or KERs) between those KEs. More help
Click to download graphical representation template Explore AOP in a Third Party Tool

Authors

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Sun-Woong Kanga, Myeong Hwa Song,Do-Sun Lim b and Kim Young Jun

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 

Point of Contact

The user responsible for managing the AOP entry in the AOP-KB and controlling write access to the page by defining the contributors as described in the next section.   More help
Young Jun Kim   (email point of contact)

Contributors

Users with write access to the AOP page.  Entries in this field are controlled by the Point of Contact. More help
  • Young Jun Kim

Coaches

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OECD Information Table

Provides users with information concerning how actively the AOP page is being developed and whether it is part of the OECD Workplan and has been reviewed and/or endorsed. OECD Project: Assigned upon acceptance onto OECD workplan. This project ID is managed and updated (if needed) by the OECD. OECD Status: For AOPs included on the OECD workplan, ‘OECD status’ tracks the level of review/endorsement of the AOP . This designation is managed and updated by the OECD. Journal-format Article: The OECD is developing co-operation with Scientific Journals for the review and publication of AOPs, via the signature of a Memorandum of Understanding. When the scientific review of an AOP is conducted by these Journals, the journal review panel will review the content of the Wiki. In addition, the Journal may ask the AOP authors to develop a separate manuscript (i.e. Journal Format Article) using a format determined by the Journal for Journal publication. In that case, the journal review panel will be required to review both the Wiki content and the Journal Format Article. The Journal will publish the AOP reviewed through the Journal Format Article. OECD iLibrary published version: OECD iLibrary is the online library of the OECD. The version of the AOP that is published there has been endorsed by the OECD. The purpose of publication on iLibrary is to provide a stable version over time, i.e. the version which has been reviewed and revised based on the outcome of the review. AOPs are viewed as living documents and may continue to evolve on the AOP-Wiki after their OECD endorsement and publication.   More help
OECD Project # OECD Status Reviewer's Reports Journal-format Article OECD iLibrary Published Version
This AOP was last modified on December 03, 2024 09:27

Revision dates for related pages

Page Revision Date/Time
HCN Channel Inhibition November 24, 2024 11:24
Reduced Pacemaker Activity in SA Node November 25, 2024 03:38
Slowed Heart Rate November 25, 2024 04:13
Altered Cardiac Electrical Conduction November 22, 2024 11:12
Occurrence, cardiac arrhythmia September 16, 2017 10:17
HCN Channel Inhibition leads to Reduced Pacemaker Activity in SA Node November 24, 2024 11:28
Reduced Pacemaker Activity in SA Node leads to Bradycardia November 24, 2024 11:29
Bradycardia leads to Altered Cardiac Electrical Conduction November 22, 2024 11:13
Altered Cardiac Electrical Conduction leads to Occurrence, cardiac arrhythmia November 22, 2024 11:14
Zatebradine November 22, 2024 11:16
Ivabradine November 22, 2024 11:15
Cilobradine November 24, 2024 11:33
Organophosphates November 29, 2016 21:20
4-bromo-2-(methylamino)-benzimidazole November 24, 2024 11:35

Abstract

A concise and informative summation of the AOP under development that can stand-alone from the AOP page. The aim is to capture the highlights of the AOP and its potential scientific and regulatory relevance. More help

The Adverse Outcome Pathway (AOP) for HCN Channel Inhibition Leading to Arrhythmias describes a mechanistic sequence linking the inhibition of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, which mediate the Funny Current (If), to the adverse outcome of cardiac arrhythmias. HCN channels are critical for maintaining diastolic depolarization in pacemaker cells of the sinoatrial (SA) node, and their inhibition disrupts cardiac pacemaker activity, leading to bradycardia, conduction abnormalities, and arrhythmias.

The pathway begins with the Molecular Initiating Event (MIE) leading to Key Event 1 (KE1): reduced pacemaker activity in the SA node, which slows heart rate (KE2: Bradycardia). Bradycardia disrupts cardiac electrical conduction (KE3: Altered Cardiac Electrical Conduction), increasing the risk of arrhythmias (Adverse Outcome). This sequence is strongly supported by experimental and clinical evidence, including dose-dependent reductions in pacemaker activity and heart rate following pharmacological HCN channel inhibition. Clinical and preclinical studies, particularly with selective If inhibitors like ivabradine, demonstrate the consistent progression from HCN inhibition to arrhythmias. Prototypical stressors include pharmacological agents such as ivabradine and zatebradine, which selectively inhibit If and are associated with bradycardia and conduction delays. Genetic mutations, such as HCN4 mutations, impair channel function and predispose individuals to arrhythmias. Environmental stressors and indirect modulators, such as electrolyte imbalances or autonomic stress, can amplify the progression of key events. This AOP provides strong biological plausibility and empirical support for early key events, though further research is needed to refine dose-response relationships and explore long-term effects of HCN inhibition. By integrating mechanistic insights with practical applications, this AOP advances understanding and assessment of cardiac arrhythmias linked to HCN channel inhibition

AOP Development Strategy

Context

Used to provide background information for AOP reviewers and users that is considered helpful in understanding the biology underlying the AOP and the motivation for its development.The background should NOT provide an overview of the AOP, its KEs or KERs, which are captured in more detail below. More help

The AOP for HCN Channel Inhibition Leading to Arrhythmias provides a mechanistic framework to understand how the inhibition of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels disrupts cardiac pacemaker function and culminates in arrhythmias. HCN channels mediate the Funny Current (If), which plays a vital role in the automaticity of sinoatrial (SA) node pacemaker cells. This current is crucial for initiating diastolic depolarization and maintaining the rhythmic contraction of the heart. Any disruption in HCN channel activity can profoundly affect cardiac electrical stability, leading to life-threatening arrhythmias. HCN channel inhibition is most commonly studied in the context of pharmacological agents, such as selective If inhibitors used to treat cardiovascular conditions. However, the pathway is also relevant to genetic mutations affecting HCN channels, indirect modulation by autonomic imbalances, and environmental factors that alter cardiac ionic currents. The AOP integrates evidence from molecular to organismal levels, providing a comprehensive framework to assess cardiotoxic risks. The pathway's applications span regulatory toxicology, drug safety evaluation, and therapeutic development. It enables the identification of cardiotoxic chemicals, informs the design of safer HCN modulators, and supports the development of diagnostic tools to predict arrhythmogenic risks. Additionally, it highlights the importance of personalized medicine approaches, such as genetic screening for HCN4 mutations, to tailor therapies and mitigate adverse outcomes.

Strategy

Provides a description of the approaches to the identification, screening and quality assessment of the data relevant to identification of the key events and key event relationships included in the AOP or AOP network.This information is important as a basis to support the objective/envisaged application of the AOP by the regulatory community and to facilitate the reuse of its components.  Suggested content includes a rationale for and description of the scope and focus of the data search and identification strategy/ies including the nature of preliminary scoping and/or expert input, the overall literature screening strategy and more focused literature surveys to identify additional information (including e.g., key search terms, databases and time period searched, any tools used). More help

1. Identify and Characterize Key Events (KEs)

1.1 Molecular Initiating Event (MIE)

Focus: Establish the inhibition of HCN channels as the molecular initiating event (MIE).

Approach:

Use in vitro electrophysiological assays (e.g., patch-clamp) to quantify HCN channel activity and the Funny Current (If).

Validate with selective HCN inhibitors (e.g., ivabradine) and their dose-dependent effects on If.

Outcome:

Define thresholds for HCN inhibition and the onset of reduced pacemaker activity.

1.2 Downstream KEs

Focus: Characterize how reduced pacemaker activity progresses to bradycardia, conduction abnormalities, and arrhythmias.

Approach:

Employ in vivo animal models and clinical data to measure:

Firing rates of sinoatrial (SA) node pacemaker cells.

Heart rate (bradycardia) using telemetry or ECG.

Electrical conduction parameters (e.g., PR interval, QRS duration).

Correlate changes in these metrics with HCN inhibition.

Outcome:

Provide mechanistic and temporal links between KEs.

2. Define Key Event Relationships (KERs)

2.1 Biological Plausibility

Focus: Establish the mechanistic rationale for each KER.

Approach:

Use computational models of cardiac electrophysiology to simulate the effects of HCN inhibition on pacemaker activity and electrical conduction.

Compare model predictions with experimental and clinical findings.

Outcome:

Support biological plausibility with experimental and modeling data.

2.2 Empirical Support

Focus: Strengthen empirical evidence for KERs through dose-response and temporal data.

Approach:

Analyze dose-response relationships between HCN inhibition, pacemaker activity, heart rate, and arrhythmias.

Document temporal concordance between the onset of KEs and the progression to arrhythmias.

Outcome:

Provide quantitative and temporal evidence for each KER.

2.3 Quantitative Understanding

Focus: Quantify relationships between KEs to predict the likelihood of the adverse outcome (AO).

Approach:

Develop dose-response curves for HCN inhibition and the severity of downstream events.

Identify thresholds for arrhythmic risk based on changes in heart rate and conduction parameters.

Outcome:

Enable predictive modeling of arrhythmias.

3. Address Modulating Factors

Focus: Evaluate how modulating factors influence the progression and severity of KEs.

Approach:

Investigate the effects of age, genetic mutations (e.g., HCN4 variants), comorbidities (e.g., heart failure), electrolyte imbalances, and sex differences.

Use subgroup analyses in preclinical and clinical studies to identify populations at higher risk.

Outcome:

Incorporate modulating factors into risk assessments and predictive models.

4. Expand Domain of Applicability

4.1 Taxonomic Applicability

Focus: Confirm the conservation of HCN channel function across species.

Approach:

Test the effects of HCN inhibition in humans, rodents, dogs, and other species using in vitro and in vivo models.

Outcome:

Establish cross-species relevance of the AOP.

4.2 Life Stage and Sex Applicability

Focus: Assess the AOP’s relevance to different life stages and sexes.

Approach:

Include juvenile, adult, and elderly models in preclinical studies.

Evaluate hormonal influences on cardiac responses to HCN inhibition.

Outcome:

Broaden the applicability of the AOP to diverse populations.

Summary of the AOP

This section is for information that describes the overall AOP.The information described in section 1 is entered on the upper portion of an AOP page within the AOP-Wiki. This is where some background information may be provided, the structure of the AOP is described, and the KEs and KERs are listed. More help

Events:

Molecular Initiating Events (MIE)
An MIE is a specialised KE that represents the beginning (point of interaction between a prototypical stressor and the biological system) of an AOP. More help
Key Events (KE)
A measurable event within a specific biological level of organisation. More help
Adverse Outcomes (AO)
An AO is a specialized KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help
Type Event ID Title Short name
MIE 2295 HCN Channel Inhibition HCN Channel Inhibition
KE 2296 Reduced Pacemaker Activity in SA Node Reduced Pacemaker Activity in SA Node
KE 2291 Slowed Heart Rate Bradycardia
KE 2292 Altered Cardiac Electrical Conduction Altered Cardiac Electrical Conduction
AO 1106 Occurrence, cardiac arrhythmia Occurrence, cardiac arrhythmia

Relationships Between Two Key Events (Including MIEs and AOs)

This table summarizes all of the KERs of the AOP and is populated in the AOP-Wiki as KERs are added to the AOP.Each table entry acts as a link to the individual KER description page. More help

Network View

This network graphic is automatically generated based on the information provided in the MIE(s), KEs, AO(s), KERs and Weight of Evidence (WoE) summary tables. The width of the edges representing the KERs is determined by its WoE confidence level, with thicker lines representing higher degrees of confidence. This network view also shows which KEs are shared with other AOPs. More help

Prototypical Stressors

A structured data field that can be used to identify one or more “prototypical” stressors that act through this AOP. Prototypical stressors are stressors for which responses at multiple key events have been well documented. More help

Life Stage Applicability

The life stage for which the AOP is known to be applicable. More help
Life stage Evidence
Not Otherwise Specified Moderate

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available. More help
Term Scientific Term Evidence Link
human and other cells in culture human and other cells in culture High NCBI
rodents rodents NCBI
dogs Canis lupus familiaris Moderate NCBI
pigs Sus scrofa NCBI
zebrafish Danio rerio Moderate NCBI

Sex Applicability

The sex for which the AOP is known to be applicable. More help
Sex Evidence
Mixed Moderate

Overall Assessment of the AOP

Addressess the relevant biological domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and Weight of Evidence (WoE) for the overall AOP as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment). More help

The AOP for HCN Channel Inhibition Leading to Arrhythmias describes a mechanistic sequence linking HCN channel inhibition to cardiac arrhythmias. It is supported by strong biological plausibility and robust empirical evidence for early key events (KEs), such as reduced pacemaker activity and bradycardia, while downstream events like conduction abnormalities and arrhythmias require further quantitative refinement. This AOP provides a robust framework for understanding and predicting arrhythmic risks due to HCN channel inhibition. While early events are well-supported, further research on later events and modulating factors will enhance its utility in regulatory applications.

Domain of Applicability

Addressess the relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context. More help
Domain  Relevance Evidence
Taxonomic Relevance Humans, rodents, dogs, pigs Clinical evidence and experimental models demonstrate conservation of HCN channel function.
Life Stage Adults, elderly Strong relevance to adult populations; some relevance in pediatric cases with congenital mutations.
Sex Both sexes Minimal sex differences observed; slight modulation by hormonal factors possible.
Molecular/Cellular Level HCN channels in SA node Primary focus on HCN4 and its role in pacemaker activity and cardiac rhythm regulation.
Stressors Ivabradine, HCN4 mutations Prototypical stressors include pharmacological agents, genetic mutations, and environmental factors.

Essentiality of the Key Events

The essentiality of KEs can only be assessed relative to the impact of manipulation of a given KE (e.g., experimentally blocking or exacerbating the event) on the downstream sequence of KEs defined for the AOP. Consequently, evidence supporting essentiality is assembled on the AOP page, rather than on the independent KE pages that are meant to stand-alone as modular units without reference to other KEs in the sequence. The nature of experimental evidence that is relevant to assessing essentiality relates to the impact on downstream KEs and the AO if upstream KEs are prevented or modified. This includes: Direct evidence: directly measured experimental support that blocking or preventing a KE prevents or impacts downstream KEs in the pathway in the expected fashion. Indirect evidence: evidence that modulation or attenuation in the magnitude of impact on a specific KE (increased effect or decreased effect) is associated with corresponding changes (increases or decreases) in the magnitude or frequency of one or more downstream KEs. More help
Key Event (KE) Essentiality Rationale and Evidence
MIE: HCN Channel Inhibition Strong Primary initiating event; inhibition directly impacts pacemaker activity and heart rate.
KE1: Reduced Pacemaker Activity Strong Essential for maintaining normal rhythm; reduced activity leads to bradycardia and conduction issues.
KE2: Slowed Heart Rate Moderate Critical intermediate step, though compensatory mechanisms may prevent progression to arrhythmias.
KE3: Altered Electrical Conduction Strong Directly linked to arrhythmias; correcting conduction abnormalities prevents downstream adverse outcomes.
AO: Arrhythmias Outcome Resulting adverse outcome of upstream disruptions; dependent on progression through earlier key events.

Evidence Assessment

Addressess the biological plausibility, empirical support, and quantitative understanding from each KER in an AOP. More help

1. Molecular Initiating Event (MIE): HCN Channel Inhibition

  • Biological Plausibility: Strong
    • HCN channels mediate the Funny Current (If), essential for diastolic depolarization in pacemaker cells.
    • HCN channel inhibition directly reduces If, slowing pacemaker activity.
  • Empirical Support: Strong
    • Ivabradine and other selective If inhibitors show dose-dependent reductions in pacemaker activity and heart rate in humans and animal models.
    • Genetic mutations in HCN4 reduce channel function and are associated with bradycardia and arrhythmias.

2. KE1: Reduced Pacemaker Activity in SA Node

  • Biological Plausibility: Strong
    • The Funny Current (If) drives diastolic depolarization; reducing If slows pacemaker firing.
    • Pacemaker activity directly influences heart rate and rhythm.
  • Empirical Support: Strong
    • Electrophysiological studies confirm reduced firing rates in SA node cells following HCN inhibition.
    • HCN4 knockout models demonstrate reduced pacemaker activity and increased susceptibility to arrhythmias.

3. KE2: Slowed Heart Rate (Bradycardia)

  • Biological Plausibility: Strong
    • Reduced pacemaker activity slows heart rate (bradycardia), increasing the risk of conduction delays and arrhythmias.
  • Empirical Support: Strong
    • Ivabradine-induced bradycardia is observed consistently in humans, dogs, and rodents.
    • ECG recordings show heart rate reductions that correlate with If inhibition.

4. KE3: Altered Cardiac Electrical Conduction

  • Biological Plausibility: Strong
    • Bradycardia increases the likelihood of conduction delays, leading to asynchronous electrical activity and reentrant circuits.
    • Conduction abnormalities (e.g., prolonged PR intervals) are precursors to arrhythmias.
  • Empirical Support: Moderate
    • ECG studies in animals and humans show conduction delays following HCN inhibition, though secondary factors (e.g., autonomic tone) may modulate effects.

5. Adverse Outcome (AO): Arrhythmias

  • Biological Plausibility: Strong
    • Arrhythmias result from electrical instability caused by conduction abnormalities, bradycardia, or asynchronous depolarization.
  • Empirical Support: Moderate
    • Clinical case reports and experimental studies link HCN inhibition and bradycardia to increased arrhythmogenic risks.
    • Arrhythmias observed in patients with HCN4 mutations provide indirect evidence.

Known Modulating Factors

Modulating factors (MFs) may alter the shape of the response-response function that describes the quantitative relationship between two KES, thus having an impact on the progression of the pathway or the severity of the AO.The evidence supporting the influence of various modulating factors is assembled within the individual KERs. More help
Modulating Factor (MF) Influence or Outcome KER(s) involved

Age

Genetic Variants

Electrolyte Imbalances

Chemical Interactions

Increased susceptibility to bradycardia and conduction delays.

HCN4 mutations amplify pacemaker dysfunction and arrhythmias.

Hypokalemia worsens bradycardia; hypercalcemia modulates risks.

β-blockers amplify bradycardia; atropine mitigates it.

HCN Inhibition → Reduced Pacemaker Activity; Reduced Activity → HR

HCN Inhibition → Reduced Pacemaker Activity; HR → Conduction Changes

Reduced Activity → HR; HR → Conduction Changes

Reduced Activity → HR; Conduction Changes → Arrhythmias

Quantitative Understanding

Optional field to provide quantitative weight of evidence descriptors.  More help
Key Event/Relationship Quantitative Evidence Thresholds Temporal Concordance
HCN Channel Inhibition (MIE) IC50 ~ 2–3 µM for If inhibition. 50% If inhibition for pacemaker effects. Seconds to minutes.
Reduced Pacemaker Activity (KE1) 50% If inhibition → 30–50% reduced activity. >40–50% If inhibition significant. Seconds to minutes.
Slowed Heart Rate (KE2) 50% If inhibition → 20–30% heart rate decrease. <50 bpm clinically significant. Minutes.
Altered Electrical Conduction (KE3) 30% HR reduction → 10–15% PR prolongation. PR > 200 ms significant. Seconds to minutes.
Arrhythmias (AO) HR < 40 bpm or PR > 250 ms → arrhythmias. Depends on heart rate and conduction. Minutes to hours.

Considerations for Potential Applications of the AOP (optional)

Addressess potential applications of an AOP to support regulatory decision-making.This may include, for example, possible utility for test guideline development or refinement, development of integrated testing and assessment approaches, development of (Q)SARs / or chemical profilers to facilitate the grouping of chemicals for subsequent read-across, screening level hazard assessments or even risk assessment. More help

The Adverse Outcome Pathway (AOP) for HCN Channel Inhibition Leading to Arrhythmias provides a mechanistic framework linking the inhibition of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, which mediate the Funny Current (If), to the adverse outcome of cardiac arrhythmias. HCN channels are critical for initiating diastolic depolarization in pacemaker cells of the sinoatrial (SA) node. Inhibition of these channels reduces pacemaker activity, leading to bradycardia, altered cardiac conduction, and arrhythmias. This AOP is supported by strong biological plausibility and robust experimental and clinical evidence. The pathway begins with the Molecular Initiating Event (MIE): HCN channel inhibition. This leads to reduced pacemaker activity in the SA node, resulting in slowed heart rate (bradycardia). Bradycardia disrupts cardiac electrical conduction, causing conduction abnormalities that increase susceptibility to arrhythmias, such as atrioventricular (AV) blocks or ventricular tachyarrhythmias. Prototypical stressors include pharmacological agents such as ivabradine and zatebradine, genetic mutations like HCN4 variants, and environmental chemicals that indirectly affect HCN channel function. This AOP has significant applications in various domains. In regulatory toxicology, it facilitates chemical screening, prioritization, and hazard identification for compounds with HCN inhibitory properties. It supports read-across approaches, enabling predictions of cardiotoxic effects in structurally or mechanistically similar chemicals. In drug development, the AOP informs preclinical safety testing, therapeutic design of HCN-targeting agents, and clinical monitoring for arrhythmic risks. Personalized medicine applications include genetic screening for HCN4 mutations and risk stratification based on individual susceptibilities. In environmental risk assessment, the AOP aids in evaluating the impact of HCN channel-inhibiting contaminants on human health and non-human species.

References

List of the literature that was cited for this AOP. More help

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.

Mesirca P, Torrente AG, Difrancesco D. Cardiac pacemaker mechanisms and their modulation by autonomic transmitters. Frontiers in Neuroscience. 2015;9:194.

Verkerk AO, Wilders R. Hyperpolarization-activated current, I(f), in mathematical models of rabbit sinoatrial node pacemaker cells. Frontiers in Physiology. 2015;6:84.

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

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.

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.

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

Stillitano F, Lonardo G, Cerbai E, et al. HCN channels and cardiac pacemaker function. Frontiers in Bioscience. 2008;13:1423–1439.

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.

Verkerk AO, van Ginneken AC, Wilders R. Pacemaker activity of the human sinoatrial node: Role of the hyperpolarization-activated current, I(f). International Journal of Cardiology. 2009;132(3):383–392.

Mesirca P, Torrente AG, Mangoni ME. Functional role of voltage-gated Ca²⁺ channels in heart automaticity. Frontiers in Physiology. 2014;5:19.

Proenza C, Yellen G. Distinct populations of HCN channel domains mediate activation and deactivation gating. Proceedings of the National Academy of Sciences. 2006;103(7):2542–2547.

Biel M, Wahl-Schott C, Michalakis S, Zong X. Hyperpolarization-activated cation channels: From genes to function. Physiological Reviews. 2009;89(3):847–885.

Baruscotti M, Robinson RB, Difrancesco D. Electrophysiological properties of the cardiac sinoatrial cells modulated by HCN channels. Frontiers in Physiology. 2016;7:173.

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

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.