• https://journals.physiology.org/doi/full/10.1152/physrev.00024.2019

• Varro - 2021

Section 1

• conduction across the heart

Section 1 establishes the central role of electrical activity in coordinating the heart’s mechanical pumping function. At the cellular level, transmembrane ion channels and transporters (particularly the fast sodium current, $I_{\text{Na}}$$I_\text{Na}$; the L-type calcium current, $I_{\text{Ca,L}}$$I_\text{Ca,L}$; and multiple potassium currents) interact to generate the cardiac action potential (AP) in a spatiotemporally regulated fashion. Key points include:

1. Origin and Propagation of the Action Potential

   • The sinoatrial (SA) node initiates spontaneous depolarizations, leveraging a specialized set of pacemaker currents (e.g., the “funny” current, $I_f$$I_f$).

   • The AP wavefront propagates through the atria to the atrioventricular (AV) node, experiences a physiological delay (in part due to lower gap junction density and smaller inward currents), and then travels via the His-Purkinje system to synchronize ventricular activation.

   • The electrocardiogram (ECG) reflects these large-scale phenomena: the P wave (atrial depolarization), QRS complex (ventricular depolarization via $I_{\text{Na}}$$I_\text{Na}$), and T wave (ventricular repolarization governed by multiple potassium and minor “late” inward currents).

2. Ionic Currents, Refractoriness, and Conduction

   • Fast inward sodium current ($I_{\text{Na}}$$I_\text{Na}$) and L-type calcium current ($I_{\text{Ca,L}}$$I_\text{Ca,L}$) critically determine upstroke velocity and conduction velocity (CV). Small changes in ion-channel density or kinetics—particularly in depolarized tissues—can alter both the safety of conduction and the magnitude of the action potential upstroke.

   • Refractoriness (effective refractory period, ERP) arises from the cumulative inactivation of inward channels and the delayed recovery of various repolarizing currents. Heterogeneities in refractoriness within or across myocardial regions amplify the potential for unidirectional conduction block.

3. Arrhythmogenic Substrates and Triggers

   • Most arrhythmias arise from a substrate (e.g., regions of fibrotic or ischemic tissue, or functionally altered myocardium) that predisposes the heart to conduction block or dispersion of repolarization, combined with a trigger (e.g., an ectopic beat).

   • Anatomical reentry (e.g., around an infarct scar) can emerge where fibrosis or nonconductive tissue provides a fixed pathway; meanwhile, functional reentry can occur purely from spatiotemporal gradients in refractoriness and conduction velocity (zig-zag conduction in partially recovered tissue).

   • Unidirectional block is key to reentry initiation: if a premature impulse travels down one pathway that has recovered excitability but is blocked in an adjacent pathway still in its refractory period, the wave can loop back retrogradely, forming a reentrant circuit.

4. Implications for Cardiac Arrhythmias

   • When action potential properties (duration, amplitude, or upstroke velocity) or cell-to-cell coupling (gap junctional conductance) are pathologically altered, conduction slows sufficiently to allow waves to find excitable gaps in previously inexcitable tissue—facilitating reentrant arrhythmias.

   • Heterogeneities in repolarization also increase the window during which ectopic beats can precipitate lethal arrhythmias (e.g., Torsades de Pointes in prolonged QT conditions).

Overall, Section 1 underscores that cardiac arrhythmias typically arise via complex, multifactorial processes involving changes in ion-channel function, refractoriness, and impulse conduction, often amplified by structural remodeling. This mechanistic insight sets the stage for the remainder of the review, which explores how specific regional differences in human cardiac electrophysiology—and their remodeling in various pathologies—can lead to significant arrhythmic risk.

Section 2

• conduction across the heart

Section 2 provides a detailed overview of the fundamental characteristics of the cardiac action potential (AP)—its ionic basis, morphological variability, and common experimental techniques to record it. Key points are:

1. Definition and Ionic Basis of the Action Potential

   • Amplitude and Resting Membrane Potential (RMP): The cardiac AP ranges from approximately −95 to +40 mV. In quiescent (non-pacemaker) myocytes, the RMP is largely governed by inwardly rectifying potassium channels (e.g., $I_{K1}$$I_{K1}$) and influenced by the electrogenic Na${}^{+}$$^+$-K${}^{+}$$^+$-ATPase, which expels 3 Na${}^{+}$$^+$ ions and imports 2 K${}^{+}$$^+$ ions per cycle.

   • Effective Refractory Period (ERP): The duration of the AP (APD) typically aligns with the ERP, so that the cell remains unexcitable until repolarization is sufficiently advanced. Under pathological conditions (e.g., hyperkalemia), postrepolarization refractoriness can occur, meaning the cell remains inexcitable despite near-complete repolarization.

2. Heterogeneity and Interspecies Variability

   • There is no uniform “cardiac AP”: significant regional differences exist in shape, duration, and plateau characteristics (nodal vs. atrial vs. ventricular, and even sub-regional differences such as endocardial vs. epicardial).

   • Interspecies differences are profound, particularly when comparing small rodents (e.g., mice, rats) to larger mammals and humans. This heterogeneity complicates extrapolation of animal-derived data to human cardiac physiology and pathology.

3. Phases of the Cardiac Action Potential

   • Phase 0 (Upstroke): Primarily driven by the fast sodium current ($I_{\text{Na}}$$I_\text{Na}$) in working myocardium, yielding a steep depolarization from the negative resting potential to positive values (overshoot).

   • Phase 1 (Initial Repolarization): A transient repolarizing “notch,” resulting from a brief outward K${}^{+}$$^+$ current (e.g., transient outward current, $I_{\text{to}}$$I_\text{to}$) and reduced inward Na${}^{+}$$^+$ conductance.

   • Phase 2 (Plateau): A prolonged depolarized plateau maintained by a balance of inward calcium (and some sodium) currents vs. outward potassium currents. In certain regions/species, this plateau can be more pronounced or nearly absent.

   • Phase 3 (Repolarization): A rapid fall in membrane potential predominantly mediated by increased K${}^{+}$$^+$ conductance (e.g., delayed rectifier currents, $I_{Kr}$$I_{Kr}$ and $I_{Ks}$$I_{Ks}$) and declining inward currents.

   • Phase 4 (Diastolic Interval): The stable RMP in non-pacemaker cells or spontaneous diastolic depolarization in pacemaker cells (e.g., SA nodal tissue) where gradual membrane depolarization eventually crosses the threshold, triggering a new AP.

4. Experimental Methods for Recording Cardiac APs

   1. Sharp Microelectrode Recordings

      • The classic technique pioneered by Weidmann, Coraboeuf, Hoffman, and Cranefield.

      • Offers high-fidelity recordings of fast voltage transients and minimal perturbation of the intracellular milieu.

      • Commonly used in tissue preparations (e.g., papillary muscles, Purkinje fibers) and allows direct measurement of RMP and AP upstroke.

      • Limitations: Maintaining stable impalements can be challenging, especially with contracting tissue.

   2. Monophasic Action Potential (MAP) Recordings

      • Used in intact hearts, in vivo or ex vivo, often with a suction electrode or Franz catheter.

      • Allows simultaneous recording of regional APs from multiple sites.

      • Trade-off: MAP recordings can distort the fast phases (upstroke and initial repolarization) and do not precisely reflect the true AP amplitude or shape.

   3. Patch Clamp in Whole-Cell Mode

      • Current-clamp recordings from isolated cardiomyocytes are widely employed to study ion-channel currents and AP morphology.

      • Major advantages: Fine control of the intracellular environment (via pipette solution) and direct measurement of ionic currents in voltage clamp.

      • Limitations:

        • Enzymatic isolation and lack of intercellular coupling may alter channel function compared to tissue.

        • Dialysis by pipette solution can disrupt native intracellular regulation.

        • Stochastic channel gating has a proportionately larger effect in single cells than in coupled tissue.

   4. Optical Mapping

      • Utilizes voltage-sensitive fluorescent dyes to record spatiotemporal AP patterns, often across large myocardial surfaces or entire ex vivo hearts.

      • Enables in-depth study of reentrant circuits and arrhythmia mechanisms.

      • Challenges:

        • Calibration to absolute membrane potentials is difficult.

        • Phototoxicity and photobleaching can affect cell viability.

        • Motion artifacts necessitate excitation-contraction uncouplers (e.g., blebbistatin), which themselves can alter cellular electrophysiology.

Overall, Section 2 underscores the complex interplay of ion channels and electrogenic transporters shaping the cardiac AP and highlights methodological considerations that influence how APs are experimentally measured. The intrinsic variability across cardiac regions and species underscores the importance of context-specific investigations, particularly when extrapolating experimental findings to human cardiac electrophysiology.

Section 3 ( Figures 4 and 6 )

• refer to the rest of section 3 for specific information about the structure/function of cardiac ion channels and transporters

  • This will be important for your understanding of Figures 4 and 6.

This part of the text focuses on the diversity and functional roles of transmembrane ion channels and transporters in human cardiac cells, highlighting the experimental methods used to characterize them and the particular ionic currents underlying different phases of the cardiac action potential. Two figures are referenced:

1. Figure 4

   • Shows a human ventricular action potential (recorded via patch clamp) and the ionic currents that shape it when the cell is paced with a human-ventricle-like voltage command.

   • Different selective inhibitors block each current in turn (e.g., blockers of IK1, IKr, IKs, Ito, ICa,L*) so that their individual contributions can be measured.

   • The diagram and data come from an experiment in which sympathetic influences (like adrenaline) are absent, isolating the baseline ionic behavior.

2. Figure 6

   • Depicts tissue-specific action potentials (human atrial, Purkinje fiber, and ventricular) and the main ionic currents responsible for each phase.

   • Arrows indicate inward (black) vs. outward (yellow) currents. Key currents include:

     • I_Na (fast sodium current)

     • I_Ca,L (L-type calcium current)

     • I_K1 (inward rectifier potassium current)

     • I_Kr / I_Ks (rapid and slow delayed rectifier potassium currents)

     • I_to (transient outward potassium current)

     • I_K,Ach (acetylcholine-activated potassium current)

     • I_Kur (ultrarapid delayed rectifier potassium current, prominent in atria)

     • I_NaL or I_NaLate (late sodium current)

     • I_f (pacemaker funny current), etc.

   • The figure also shows modulatory factors (e.g., Ca²⁺-calmodulin kinase II, β-adrenergic influence, toxins like tetrodotoxin) and the molecular identities of channels (e.g., hERG for I_Kr, Nav for sodium channels, Kir or Kv for potassium channels).

Together, these references illustrate how each type of cardiac cell region (atria, Purkinje fibers, ventricles) exhibits distinct action potential shapes because they express different densities and types of ion channels. In turn, these ion channels are crucial for:

• Initiation and propagation of electrical signals (via sodium or calcium currents)

• Repolarization (via potassium currents like I_Kr, I_Ks, and I_K1)

• Pacemaker activity (via I_f or spontaneous diastolic depolarization currents)

• Regulation by neuromodulators (e.g., parasympathetic via acetylcholine-activated potassium current I_K,Ach; sympathetic via β-adrenergic effects).

In essence, Section 3 and its figures highlight that cardiac excitability and arrhythmogenesis hinge on the precise interplay of specialized ionic currents, each finely tuned in different parts of the heart.

Section 4 ( everything but 4.3 )

• the ionic basis of various action potentials in the heart

1. Sinoatrial (SA) Node and Pacemaker Function

   • The SA node (SAN) is the heart’s natural pacemaker, generating spontaneous action potentials that set the normal heart rate.

   • SAN cells have a lower diastolic potential (around −60 mV) and gradually depolarize during diastole until reaching threshold for L-type Ca²⁺ channels.

   • Historically, the funny current (I_f) was seen as the primary pacemaking current. However, the “coupled clock” hypothesis proposes that both I_f (“membrane clock”) and intracellular Ca²⁺ cycling (“calcium clock,” involving the Na⁺-Ca²⁺ exchanger) drive automaticity.

   • SAN cells are relatively lacking in fast sodium current (I_Na). Instead, L-type Ca²⁺ current (I_Ca,L) is the main depolarizing current.

   • Intracellular second messengers (e.g., cAMP) strongly modulate pacemaker rate; vagal stimulation lowers cAMP and slows SAN rate, while sympathetic tone does the opposite.

2. Atrial Action Potential

   • Atrial action potentials differ markedly across species and even within the same heart, lacking a long plateau in most animals—though human atria may show a modest plateau near −10 to −30 mV.

   • Key outward currents include I_to and I_Kur, which shape early repolarization. I_Kur is prominent in atria but largely absent in ventricles.

   • Neurohormonal influences (acetylcholine, catecholamines, substance P, etc.) modulate atrial repolarization. For example, I_K,ACh (acetylcholine-activated K⁺ current) can shorten the atrial action potential and is increased in chronic atrial fibrillation.

3. AV Nodal Action Potential and Conduction

   • AV node cells resemble SAN cells in some respects (e.g., reliance on I_Ca for conduction) but have even lower pacemaker rates and a more negative maximal diastolic potential.

   • They lack significant fast Na⁺ current, explaining slower conduction, which physiologically creates the delay between atrial and ventricular contractions.

   • Adenosine (via I_K,ACh) and acetylcholine can hyperpolarize AVN cells, slowing or blocking conduction—a mechanism exploited in stopping AV nodal reentrant tachycardias.

4. Purkinje Fiber Action Potential

   • Purkinje fibers rapidly deliver electrical impulses through the ventricles and can serve as backup pacemakers.

   • They display a long APD compared to ventricular muscle and can exhibit early or delayed afterdepolarizations (EADs/DADs) under certain pathophysiological conditions.

   • Their specialized ionic profile (including a robust I_f, slow-inactivating Na⁺ current, and sometimes T-type Ca²⁺ current) and weaker electrical coupling to surrounding tissue can predispose Purkinje fibers to ectopic activity.

5. Ventricular Action Potentials: Transmural and Regional Differences

   • Ventricular myocytes generally have a pronounced plateau (+20 to +30 mV), but subepicardial, midmyocardial, and subendocardial cells differ in phase 1 notch (I_to density) and action potential duration.

   • These variations create transmural gradients that can become proarrhythmic if they are exaggerated (e.g., by ischemia or drugs).

   • Left–right and apex–base differences also exist; for example, the left ventricle often has longer APDs than the right ventricle.

6. Species-Dependent Differences

   • Rodents (mice/rats) have much shorter action potentials, often without a clear plateau, owing to different ion channel expression (e.g., prominent I_to and I_Kur).

   • Larger mammals (e.g., dogs, rabbits, guinea pigs) and humans have more substantial plateaus and rely more on I_Kr, I_Ks, etc.

   • These differences complicate extrapolation from animal models to humans—particularly for drug testing and arrhythmia research—though rodents remain useful for genetic manipulation studies.

   • Human iPSC-derived cardiomyocytes offer a promising new approach but still face hurdles (e.g., incomplete maturation, different resting potentials) before fully replacing animal models.

In sum, Section 4 underscores that action potential shape and ion channel expression vary substantially across different regions of the heart and among species. These distinctions are vital for understanding normal cardiac function, arrhythmia mechanisms, and the translational challenges in developing antiarrhythmic therapies.

Section 6

• arrhythmias

Section 6 examines how cellular-level alterations in membrane potential and calcium handling can generate arrhythmic triggers and substrates. It covers (1) abnormal depolarization reducing conduction safety, (2) triggered automaticity via early or delayed afterdepolarizations, (3) the rate dependence of action potentials (restitution), and (4) the emergence of repolarization alternans and short-term variability—collectively providing fundamental mechanistic insights into how arrhythmias initiate and sustain in diseased myocardium.

6.1. Depolarization Abnormalities

• Reduced INa or partial membrane depolarization (e.g., due to ischemia) can cause conduction slowing/block, a key substrate for reentry.

• Brugada syndrome exemplifies pathological INa loss-of-function, though L-type Ca${}^{2+}$$^{2+}$ and Ito changes also contribute to phase 2 reentry and arrhythmogenesis.

• Upregulated If in diseased ventricles or atria (e.g., in heart failure) may increase the likelihood of ectopic depolarizations that trigger tachyarrhythmias.

6.2. Triggered Automaticity

Triggered automaticity is an abnormal spontaneous activity that requires a prior action potential; it is subdivided into early afterdepolarizations (EADs) and delayed afterdepolarizations (DADs) based on when they occur relative to the preceding AP.

6.2.1. Early Afterdepolarizations (EADs)

• EADs arise during the AP, typically in phase 2 or 3, and are often linked to marked AP prolongation (e.g., reduced IKr).

• Mechanisms:

  1. Reactivation of L-type Ca${}^{2+}$$^{2+}$ channels (“window current”) if the plateau persists long enough.

  2. Ca${}^{2+}$$^{2+}$ release and subsequent forward-mode NCX current if Ca${}^{2+}$$^{2+}$ spontaneously leaks from the SR during repolarization.

  3. Late INa can also play a role when it fails to inactivate properly.

• Dynamic interplay: NCX, IKr gating kinetics (inactivation vs. recovery), and CaMKII/PKA-mediated phosphorylation modulate EAD vulnerability.

6.2.2. Delayed Afterdepolarizations (DADs)

• DADs occur after repolarization during diastole and are classically associated with SR Ca${}^{2+}$$^{2+}$ overload (e.g., in digitalis toxicity, heart failure, or CPVT).

• The key driver is spontaneous SR Ca${}^{2+}$$^{2+}$ release that activates forward-mode NCX, depolarizing the membrane until it can trigger a new AP.

• Calcium waves and sparks must synchronize to produce sufficient inward current to overcome the stabilizing IK1.

6.2.3. Tissue-Level Propagation of Afterdepolarizations

• While single-cell EADs/DADs may not necessarily propagate in well-coupled myocardium, moderate gap junction uncoupling (e.g., in infarct border zones) reduces electrotonic sink and can allow small populations of myocytes exhibiting EADs/DADs to trigger a reentrant wave.

• Computational modeling indicates that pathological changes (fibrosis, heart failure, conduction slowing) can reduce the critical mass needed for an afterdepolarization to spread, highlighting how disease remodeling magnifies the proarrhythmic impact of triggered activity.

6.3. Frequency Dependence and Restitution

• AP duration (APD) and impulse conduction exhibit characteristic rate dependence: APD generally shortens at faster heart rates and prolongs at slower rates.

• Electrical restitution describes how APD adapts to varying diastolic intervals.

  • A steep restitution slope is considered proarrhythmic, as it can produce large beat-to-beat changes in repolarization, predisposing to conduction block and reentry.

  • Flattening the restitution curve can stabilize repolarization and reduce arrhythmic risk.

• Ionic mechanisms: incomplete deactivation/recovery of INa, ICa, Ito, IKr, IKs, and dynamic changes in intracellular/extracellular ions (especially K${}^{+}$$^+$ in narrow clefts) underlie rate-dependent electrophysiological behaviors.

6.4. Repolarization Alternans and Temporal Variability

1. Alternans

   • AP alternans manifests as alternating long–short APD at rapid heart rates, often in concert with intracellular Ca${}^{2+}$$^{2+}$ transient alternans.

   • Mechanistic explanations typically focus on:

     • Steep APD restitution (“voltage-driven” alternans), or

     • Ca${}^{2+}$$^{2+}$-cycle-driven alternans (release-reuptake mismatch and/or RyR refractoriness).

   • Discordant alternans (opposite-phase oscillations in different regions) critically heightens repolarization dispersion and fosters reentrant arrhythmias.

2. Short-Term Variability and Arrhythmogenicity

   • Beat-to-beat fluctuations in APD or QT intervals (short-term variability) often precede torsade de pointes or ventricular fibrillation.

   • Mechanisms may include stochastic ion-channel gating, Ca${}^{2+}$$^{2+}$-handling variability, and interplay with NCX or other currents.

Overall Significance

Section 6 underscores the tight interplay between ion-channel gating, intracellular Ca${}^{2+}$$^{2+}$ dynamics, and cell-to-cell coupling, which together determine whether afterdepolarizations or alternans remain subcellular phenomena or spark full-blown reentrant arrhythmias. Crucially, diseases such as ischemic heart disease, heart failure, hypertrophic cardiomyopathy, and genetic channelopathies remodel these processes, amplifying triggered activity and conduction heterogeneities. Consequently, the same cellular mechanisms (EADs, DADs, steep restitution, alternans) that are benign in healthy tissue can become potent arrhythmogenic drivers under pathological conditions, guiding therapeutic and research efforts aimed at preventing lethal arrhythmias.