Purkinje Fibers Research Articles

Moderator Band and Ventricular Tachycardia: Structural or Functional Substrate?

The moderator band (MB) is an intracavitary structure of the right ventricle composed of muscular fibers encompassing specialized Purkinje fibers, separated each other by collagen and adipose tissue. In the last decades, premature ventricular complexes originating within the Purkinje network have been implicated in the genesis of life-threatening arrhythmias. However, right Purkinje network arrhythmias have been much less reported in the literature compared to the left counterpart. The MB has unique anatomical and electrophysiological properties, which may account for its arrhythmogenicity and may be responsible for a significant portion of idiopathic ventricular fibrillation. MB embodies autonomic nervous system cells, with important implications in arrhythmogenesis. Some idiopathic ventricular arrhythmias, defined as the absence of any identifiable structural heart disorder, can begin from this site. Due to these complex structural and functional peculiarities strictly interplayed each other, it is arduous to determine the precise mechanism underlying MB arrhythmias. MB-related arrhythmias should be differentiated from other right Purkinje fibers arrhythmias because of the opportunity for intervention and the unusual site for the ablation poorly described in the literature. In the current paper, we report the characteristics and electrical properties of the MB, their involvement in arrhythmogenesis, clinical and electrophysiological peculiarities of MB-related arrhythmias, and current treatment options.

Coexisting Behavior and Status Transition of the Hodgkin-Huxley Cardiac Purkinje Fiber Model Under External AC Injection

The membrane current I_m of the Hodgkin-Huxley (HH) cardiac Purkinje fiber (CPF) model is usually calculated as direct current (DC). In this paper, a conventional alternating current (AC) is used, namely I_{AC} = textrm{Asin}(2 pi ft), as the impressed injection. Dynamic characters of the model with different AC parameters and various initial conditions are observed through phase plane orbits, waveforms, bifurcation diagrams, and Lyapunov exponent spectra, which reveal multiple coexisting membrane action potential patterns, corresponding to the coexisting attractors of the same or different periods in the phase diagram. Meanwhile, the model undergoes period, quasi-period and local forward or inverse period-doubling bifurcations with changes in amplitude A or frequency f, which further proves the complex nonlinear property of the AC-injected model. In addition, by changing the external current I_m, the sodium-ion and potassium-ion equilibrium potentials, i.e. E_{Na} and E_{K}, respectively, the regularity of the CPF heartbeat frequency is observed. The state transformations of CPF are found between normal, abnormal and sudden cardiac arrest, and the method adjusting from the dangerous state to the normal heartbeat frequency range is investigated. This study may provide a reference for exploring the evolution of nonlinear dynamics in HH CPF model and protecting the health of life and heart.

ActionPytential: An open source tool for analyzing and visualizing cardiac action potential data

The action potential forms the basis of cardiac pacemaking, conduction, and contraction. Action potentials can be recorded from numerous preparation types, including ventricular or atrial trabecules, Purkinje fibers, isolated cardiac myocytes. Numerous techniques are also available as well, such as the conventional microelectrode and the single-cell current clamp techniques, optical mapping, or in silico modeling. With such a vast array of electrophysiological methods comes an array of available hardware and software solutions. In this work, we present a software with an intuitive graphical user interface, ActionPytential, that enables the analysis of any type of cardiac action potential, regardless of acquisition method or tissue type.In most available software tools, the analysis of continuous (gap-free) recordings often requires manual user interaction to segment the individual action potentials. We provide an automated solution for this, both for slow-response and for externally paced action potentials. As of now, ActionPytential calculates 34 parameters from each action potential. The most often utilized ones, including amplitude, maximal rate of depolarization, and action potential duration values, were validated on 1200 action potentials from human, dog, rabbit, guinea pig, and rat cardiac preparations. We also provide new parameters that were previously only measurable manually, including the position and the depth of the notch in potentials showing a spike-and-dome morphology. Further notable features include a Butterworth-type low-pass filter, the averaging of multiple potentials, automated corrections for baseline drifting, aided manual analysis, high-quality plots, and batch processing for any number of potentials.ActionPytential is available for all major platforms (Windows, MacOS, GNU + Linux, BSD).

A rapid wide complex tachycardia

A rapid wide complex tachycardia

Testing the nonclinical Comprehensive In Vitro Proarrhythmia Assay (CiPA) paradigm with an established anti-seizure medication: Levetiracetam case study.

Levetiracetam (LEV), a well-established anti-seizure medication (ASM), was launched before the original ICH S7B nonclinical guidance assessing QT prolongation potential and the introduction of the Comprehensive In Vitro Proarrhythmia Assay (CiPA) paradigm. No information was available on its effects on cardiac channels. The goal of this work was to "pressure test" the CiPA approach with LEV and check the concordance of nonclinical core and follow-up S7B assays with clinical and post-marketing data. The following experiments were conducted with LEV (0.25-7.5 mM): patch clamp assays on hERG (acute or trafficking effects), NaV 1.5, CaV 1.2, Kir 2.1, KV 7.1/mink, KV 1.5, KV 4.3, and HCN4; in silico electrophysiology modeling (Virtual Assay® software) in control, large-variability, and high-risk human ventricular cell populations; electrophysiology measurements in human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes and dog Purkinje fibers; ECG measurements in conscious telemetered dogs after single oral administration (150, 300, and 600 mg/kg). Except a slight inhibition (<10%) of hERG and KV 7.1/mink at 7.5 mM, that is, 30-fold the free therapeutic plasma concentration (FTPC) at 1500 mg, LEV did not affect any other cardiac channels or hERG trafficking. In both virtual and real human cardiomyocytes, and in dog Purkinje fibers, LEV induced no relevant changes in electrophysiological parameters or arrhythmia. No QTc prolongation was noted up to 2.7 mM unbound plasma levels in conscious dogs, corresponding to 10-fold the FTPC. Nonclinical assessment integrating CiPA assays shows the absence of QT prolongation and proarrhythmic risk of LEV up to at least 10-fold the FTPC and the good concordance with clinical and postmarketing data, although this does not exclude very rare occurrence of QT prolongation cases in patients with underlying risk factors.

Old but not Vain : Two Cases of Refractory Polymorphic Ventricular Tachycardia associated with Coronary Artery Disease successfully treated with Quinidine

Post myocardial infarct polymorphic Ventricular Tachycardia (VT) triggered by injured Purkinje fibres can cause VT storms that are refractory to various treatment even after successful reperfusion or revascularization. We reported such recurrent polymorphic VT in two post myocardial infarct patients after Percutaneous Coronary Intervention. Both of them responded readily to Quinidine. We also discussed the pathophysiology of this arrhythmia and the treatment option of it, namely catheter ablation and antiarrhythmics

Catheter ablation of idiopathic left fascicular ventricular tachycardia: Implications of false tendons for mapping and ablation.

The anatomical substrate for idiopathic left ventricular tachycardia (ILVT) remains speculative. Purkinje networks surrounding false tendons (FTs) might be involved in the reentrant circuit of ILVT. The objective was to evaluate the anatomical and electrophysiological features of false tendons FTs in relation to ILVT. Intracardiac echocardiography (ICE) was conducted on patients with ILVT. The relationship of the FTs with ILVT was determined using electro-anatomical mapping. Electrophysiological evaluation and radiofrequency ablation were conducted in 23 consecutive patients with ILVT. FTs were identified in 19/23 cases (82.6%) with P1 potentials during VT recorded at the FT in 14 of these patients (73.7%). Three FT types were identified. In type 1, the FT attached the septum to the base of the posteromedial papillary muscle (PPM) (4/19); type 2 FTs ran between the septum and the PPM apex (3/19), while in type 3, the connection occurred between the septum and apex (11/19) or between the septum and the LV free wall (1/19). The effective ILVT ablation sites were situated at the FT-PPM (3/19) and the FT-septum (16/19) attachment sites. This series demonstrates the association between Purkinje fibers and FTs during catheter ablation of ILVT and verifies that left ventricular FTs are an important substrate in this type of tachycardia.

Intramural Purkinje fibers facilitate rapid ventricular activation in the equine heart.

The Purkinje fibers convey the electrical impulses at much higher speed than the working myocardial cells. Thus, the distribution of the Purkinje network is of paramount importance for the timing and coordination of ventricular activation. The Purkinje fibers are found in the subendocardium of all species of mammals, but some mammals also possess an intramural Purkinje fiber network that provides for relatively instantaneous, burst-like activation of the entire ventricular wall, and gives rise to an rS configuration in lead II of the ECG. To relate the topography of the horse heart and the distribution and histology of the conduction system to the pattern of ventricular activation as a mechanism for the unique electrical axis of the equine heart. The morphology and distribution of the cardiac conduction system was determined by histochemistry. The electrical activity was measured using ECG in the Einthoven and orthogonal configuration. The long axis of the equine heart is close to vertical. Outside the nodal regions the conduction system consisted of Purkinje fibers connected by connexin 43 and long, slender parallel running transitional cells. The Purkinje fiber network extended deep into the ventricular walls. ECGs recorded in an orthogonal configuration revealed a mean electrical axis pointing in a cranial-to-left direction indicating ventricular activation in an apex-to-base direction. The direction of the mean electrical axis in the equine heart is determined by the architecture of the intramural Purkinje network, rather than being a reflection of ventricular mass.

Endocardial role in arrhythmias induced by acute ventricular stretch and the involvement of Purkinje fibres, in isolated rat hearts

Purkinje fibres (PFs) play an important role in some ventricular arrhythmias and acute ventricular stretch can evoke mechanically-induced arrhythmias. We tested whether PFs and specifically TRPM4 channels, play a role in these mechanically-induced arrhythmias. Pseudo-ECGs and left ventricular (LV) activation, measured by optical mapping, were recorded in isolated, Langendorff-perfused, rat hearts. The LV endocardial surface was irrigated with experimental agents, via an indwelling catheter. The number and period of ectopic activations was measured during LV lumen inflation via an indwelling fluid-filled balloon (100 μL added over 2 s, maintained for 38 s). Mechanically-induced arrhythmias occurred during balloon inflation: they were multifocal, maximal in the first 5 s and ceased within 20 s. Optical mapping revealed activation patterns indicating PF-mediated and ectopic focal sources. Irrigation of the LV lumen with Lugol solution (IK/I2) for 10s reduced ectopics by 93% (n = 16, P < 0.001); with ablation of endocardial PFs confirmed by histology. Five min irrigation of the LV lumen with 50 μM 9-Phenanthrol, a blocker of TRPM4 channels, reduced ectopics by 39% (n = 15, P < 0.01). Immunohistochemistry confirmed that TRPM4 was more abundant in PFs than myocardium. Our results show that the endocardial surface plays an important role in these mechanically-induced ectopic activations. Ectopic activation patterns indicate a participation of PFs in these arrhythmias, with a potential involvement of TRPM4 channels, shown by the reduction of arrhythmias by 9-Phenanthrol.

Aquatic environments change the cardiac morphology of dolphins.

Previous studies on dolphin electrocardiograms have shown that they are mainly composed of increased negative waves, similar to ungulates. The electrocardiogram waveform was determined by the distribution of the Purkinje fibers. Based on the waveform of the dolphin electrocardiogram, Hamlin predicted that the Purkinje fibers would be distributed within the ventricular muscle, as in ungulates. The purpose of this study was to confirm the histological distribution of Purkinje fibers in dolphins. In the present study, bottlenose dolphin hearts were observed both grossly and histologically, and the effects of Purkinje fiber distribution and cardiac morphology on electrocardiogram waveforms were examined. This study showed that the Purkinje fibers of dolphins run just below the endocardium, as in humans, dogs, and cats, whose electrocardiograms mainly show positive waves. When the cardiac morphology of dolphins was observed carefully, the right ventricle was found to be extremely dilated compared to that of terrestrial mammals. In human recreational divers, right ventricular dilatation is induced by diving. We hypothesized that the dolphin's heart is in a state similar to that of the right heart dilatation in terrestrial animals. The dolphin electrocardiogram waveform was considered to be due to right axis deviation. Based on the above, we concluded that the dolphin electrocardiogram waveform was due to its ability to live in water. We found that the dolphins are genetically related to ungulates, particularly the hippopotamus, but that their hearts have evolved differently.

Repetitive multiform narrow complex tachycardia

A 73-year-old man presented to the emergency department with palpitations. After experiencing transient exertional palpitations and dyspnea a few months earlier, investigation revealed moderate left ventricular dysfunction and extensive coronary artery disease with evidence of prior inferior infarction. He underwent bypass grafting and remained symptom free with normalization of his ejection fraction until the current presentation. Figure 1 demonstrates his presenting rhythm that did not respond to adenosine but terminated with intravenous diltiazem. What is the most likely mechanism of the tachycardia? Figure 1 shows a regular narrow complex tachycardia with 3 distinct alternating QRS morphologies: (1) right bundle branch block (RBBB), V1 R 120 ms, V4 precordial transition, left superior axis; (2) RBBB, V1 rsRʹ 100 ms, positive precordial concordance, left superior axis; and (3) RBBB, V1 R 100 ms, positive precordial concordance, left superior axis. The RBBB and left superior axis of all 3 morphologies suggest that the ventricles are activated via the left posterior fascicle, or at the very least, there is early engagement of this fascicle. While supraventricular tachycardia with aberrant conduction is theoretically possible, varying ventricular morphologies in this fashion, lack of termination with adenosine, and the relatively narrow QRS duration (<130 ms) would make this less likely. Together with the response to diltiazem, the overall evidence suggests ventricular tachycardia involving the left posterior fascicle. The classic form of idiopathic fascicular ventricular tachycardia involves the left posterior fascicle, in which there is slow antegrade conduction along abnormal Purkinje fibers in the mid-septum (resulting in P1 potentials) and conduction over the left posterior fascicle (resulting in P2 potentials).1Nogami A. Naito S. Tada H. et al.Demonstration of diastolic and presystolic Purkinje potentials as critical potentials in a macroreentry circuit of verapamil-sensitive idiopathic left ventricular tachycardia.J Am Coll Cardiol. 2000; 36: 811-823Crossref PubMed Scopus (218) Google Scholar In any individual patient, variable relationships of the abnormal Purkinje fiber to the left posterior fascicle can result in a more basal or apical site of breakout to the left ventricle; these differences can often be suggested on the surface electrocardiogram by the width of the QRS complex and the precordial transition.2Liu Q. Shehata M. Jiang R. et al.Macroreentrant loop in ventricular tachycardia from the left posterior fascicle: new implications for mapping and ablation.Circ Arrhythm Electrophysiol. 2016; 9e004272Crossref Scopus (7) Google Scholar,3Ma W. Lu F. Shehata M. et al.Catheter ablation of idiopathic left posterior fascicular ventricular tachycardia: predicting the site of origin via mapping and electrocardiography.Circ Arrhythm Electrophysiol. 2017; 10e005240Crossref PubMed Scopus (1) Google Scholar Sung et al4Sung R.K. Kim A.M. Tseng Z.H. et al.Diagnosis and ablation of multiform fascicular tachycardia.J Cardiovasc Electrophysiol. 2013; 24: 297-304Crossref PubMed Scopus (29) Google Scholar described multiform fascicular QRS complexes due to alternate conduction over the left anterior fascicle and the left posterior fascicle from the septal fascicle, but the QRS forms described in the present report are different. Idiopathic fascicular ventricular tachycardia typically occurs in patients with structurally normal hearts, which was not the case in the present report. However, abnormal Purkinje fibers have also been implicated in a minority of patients with ischemic ventricular tachycardia and extension of inferoposterior scar to the left posterior fascicle.5Bogun F. Good E. Reich S. et al.Role of Purkinje fibers in post-infarction ventricular tachycardia.J Am Coll Cardiol. 2006; 48: 2500-2507Crossref PubMed Scopus (121) Google Scholar In this case, it was hypothesized that different QRS morphologies were due to varying sites of left ventricular breakout (Figure 2). The patient underwent electrophysiology study, where multiple episodes of ventricular tachycardia were able to be induced with ventricular extrastimuli similar to those seen on presentation. Ablation of the left posterior fascicle was undertaken, with subsequent noninducibility and no further episodes after 12 months of follow-up.

Diffuse and Massive Endocardial Sarcocystosis in a Lamb

Sarcocystosis is a critical parasitic zoonosis caused by Sarcocystis species, an intracellular protozoan parasite of the Apicomplexa phylum and one of the most prevalent parasitic diseases among wild and domestic animals all around the world. Infection in the definitive host is mainly characterized by the formation of cysts in muscle tissue. In intermediate host skeletal muscles, the diaphragm and heart are the favored locations for Sarcocystis spp. While we were examining the heart of a three-month-old dead lamb, we incidentally observed striking, white, and discrete spots, measuring 2–3 mm, that were diffusely distributed in the endocardium. Microscopically, numerous Sarcocystis were seen within cardiomyocytes and Purkinje fibers. No different pathological modifications had been found in inflamed muscle fibers or the surrounding interstitium. To the best of our knowledge, there is no case report about diffuse involvement of endocardium by Sarcocystis spp., and this unique form of sarcocystosis prompted us to place the current case on record.

Computational based approach to analyze Sodium (Na + ) channels effects in Purkinje fiber cells for action potential Phase 1 using Euler integration method - a simulation study

Purkinje Fibre Cell (PFC) is the biological network to synchronization and coordination with the ventricular myocardium. PFC electrical activities are generated with different ion channels. In that Sodium (Na + ) channel is responsible for the production of Phase 1 Action Potentials (AP). Human PFC AP was generated using Aslandi’s Model (ADM), which was based on human endocardial cells. ADM ionic currents are based on Han’s experimental data, and it also describes the properties of Na + channels and their density in human PFC. ADM of human PFC is solved by Innovative Euler Integration Method (EIM) with Matlab software for various Na + channel failure conditions with a same group of 100, threshold of 0.05, G Power of 80 %, confidence interval of 95 %, and enrolment ratio of 1. The results are also verified by using Statistical Package for the Social Sciences (SPSS). The normal Na + conductance in Na + channel (GNa) is 130.57nS, which has AP duration (APD) in the range of 0 ms to 98 ms. In the increased condition of deviant GNa = 260nS having APD in the range of 20 ms to 25 ms. Similarly, in the decreased condition of deviant GNa = 2nS having APD in the range of 20 ms to 140 ms. The different dysfunctional pairs seemed to be significant between most of the pairs (p < 0.05). Subcellular localization of Na + channel subunits (conductance) in human PFC myocardium produces alternants in APD. Alternants in APD is a major source for life threatening cardiac arrhythmias, synchronization and coordination failure with the ventricular myocardium, as well as Excitation-Contraction (EC) coupling.

Biventricular false tendons

Biventricular false tendons

What acute cardiac care physicians need to know from the latest 2022 ESC Guidelines for ventricular tachycardia and sudden cardiac death.

The present paper summarizes and comments on the latest 2022 ESC guidelines on ventricular tachycardia and sudden cardiac death. Most relevant recommendations for acute cardiovascular care physicians are addressed, particularly, in the fields of coronary artery disease, dilated cardiomyopathy, and inflammatory diseases. New recommendations encompass the implantation of a defibrillator (ICD) in the setting of acute myocarditis. Furthermore, the pathophysiology of the electrical storm including involved molecular pathways as well as the angry Purkinje fibre syndrome is presented and discussed.

Cerebellar Hypoplasia in Two Juvenile African Grey Parrots (Psittacus erithacus).

Two sibling 12-week-old DNA-sexed female African grey parrots (Psittacus erithacus) were presented for progressive whole-body tremors, proprioceptive deficits, and an inability to stand unassisted. A third bird in the clutch (DNA-sexed as a male) exhibited no clinical signs. Physical examination of the affected birds revealed ataxia, inability to stand without assistance, and a reliance on their beaks to assist with their mobility. Hematologic and biochemical analyses were normal, as were radiographic images of both birds. Cerebellar disease of unknown origin was diagnosed, and the birds were euthanized. Postmortem examinations of the brains of both parrots revealed marked reduction in cerebellar size and poor folia formation. Microscopic review of the cerebellums demonstrated decreased density of the granular layer and thinning of the molecular layer with poorly organized and differentiated Purkinje fibers, consistent with a diagnosis of cerebellar hypoplasia. There are limited clinical reports and experimental studies examining cerebellar disease in birds. Conditions described have included cerebellar hypoplasia, cerebellar abiotrophy, and cerebellar dysplasia. Although these terms are used interchangeably due to similar clinical signs, histopathology is needed to differentiate between the different disease conditions. This case describes cerebellar hypoplasia that suggested a developmental etiology in 2 African grey parrots.

Acetylcholine Reduces L-Type Calcium Current without Major Changes in Repolarization of Canine and Human Purkinje and Ventricular Tissue.

Vagal nerve stimulation (VNS) holds a strong basis as a potentially effective treatment modality for chronic heart failure, which explains why a multicenter VNS study in heart failure with reduced ejection fraction is ongoing. However, more detailed information is required on the effect of acetylcholine (ACh) on repolarization in Purkinje and ventricular cardiac preparations to identify the advantages, risks, and underlying cellular mechanisms of VNS. Here, we studied the effect of ACh on the action potential (AP) of canine Purkinje fibers (PFs) and several human ventricular preparations. In addition, we characterized the effects of ACh on the L-type Ca2+ current (ICaL) and AP of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and performed computer simulations to explain the observed effects. Using microelectrode recordings, we found a small but significant AP prolongation in canine PFs. In the human myocardium, ACh slightly prolonged the AP in the midmyocardium but resulted in minor AP shortening in subepicardial tissue. Perforated patch-clamp experiments on hiPSC-CMs demonstrated that 5 µM ACh caused an ≈15% decrease in ICaL density without changes in gating properties. Using dynamic clamp, we found that under blocked K+ currents, 5 µM ACh resulted in an ≈23% decrease in AP duration at 90% of repolarization in hiPSC-CMs. Computer simulations using the O'Hara-Rudy human ventricular cell model revealed that the overall effect of ACh on AP duration is a tight interplay between the ACh-induced reduction in ICaL and ACh-induced changes in K+ currents. In conclusion, ACh results in minor changes in AP repolarization and duration of canine PFs and human ventricular myocardium due to the concomitant inhibition of inward ICaL and outward K+ currents, which limits changes in net repolarizing current and thus prevents major changes in AP repolarization.

Abstract 13963: Short-Coupled Variant of Torsade de Pointes: A Rare Entity With Unknown Etiology and Malignant Phenotype

Introduction: Torsade de Pointe (TdP) is defined as a polymorphic VT (pVT) typically associated with QTc prolongation. However, not all pVT occur in the presence of QTc prolongation and respond to different forms of therapy. Hence defining their etiology is important. Case: A 48-yo Female with H/O resolved peripartum cardiomyopathy, hypertension &amp; obesity presented to the hospital following a syncopal episode. Her BP was 207/125 mmHg, and ECG showed sinus rhythm with a QTc of 436. No history of heart disease or SCD in her family. Physical exam was unremarkable, labs showing K-3.2 without troponin elevation. On day 2, she developed a pVT requiring defibrillation and amiodarone. Telemetry revealed a PVC causing R on T phenomenon with a coupling interval of 260 msec prior to initiation of SVT with QTc 484 and K-2.8. On day 3, despite electrolyte correction, she had multiple non-sustained pVTs with QTc 482. Amiodarone was switched to lidocaine and QTc normalized to 447. TTE and LHC were unremarkable with a small LV aneurysm on cMRI. On day 4, the patient continued to have incessant runs of pulseless pVT requiring defibrillation and started on verapamil. A 12 lead ECG during VT demonstrated left bundle branch mimicry with a left axis consistent with a VT exit site along the RV moderator band. The patient underwent emergent ablation with targets along the right anterolateral papillary muscle. AICD was placed prior to discharge. Discussion: The critical timing of PVC falling on the peak of the preceding T wave differentiates ‘Short-coupled TdP’ from other malignant VTs with normal QTc. These PVCs typically originate from distal ramifications of Purkinje fibers in both ventricles. PVC morphology with LBBB pattern, left axis and late precordial R-S transition points to the moderator band as the source of idiopathic VT. Contrasting with typical TdP, medical management with Quinidine and Verapamil may be efficacious. Catheter ablation is curative in most cases.

Selective sparing of Purkinje fibres with pulsed-field myocardial ablation.

Selective sparing of Purkinje fibres with pulsed-field myocardial ablation.

When Is a Potassium Channel Not a Potassium Channel?

Ever since they were first observed in Purkinje fibers of the heart, funny channels have had close connections to potassium channels. Indeed, funny channels were initially thought to produce a potassium current in the heart called I K2. However, funny channels are completely unlike potassium channels in ways that make their contributions to the physiology of cells unique. An important difference is the greater ability for sodium to permeate funny channels. Although it does not flow through the funny channel as easily as does potassium, sodium does permeate well enough to allow for depolarization of cells following a strong hyperpolarization. This is critical for the function of funny channels in places like the heart and brain. Computational analyses using recent structures of the funny channels have provided a possible mechanism for their unusual permeation properties.