A. Cardiac Action Potential [1,2]
[Figure] "Cardiac Cell Action Potentials"

1. Action Potential (AP) - firing of electrically active cell
   1. AP begins in PHASE 0,1
   2. AP continues through PHASE 2 until repolarization
   3. AP is coupled to muscle contraction (cardiac, skeletal) or nerve conduction (neurons)
2. Action Potential Phases
   1. Phase 0 - depolarization begins, rapid increase in membrane voltage
   2. Phase 1 - slowed increase in membrane depolarization
   3. Phase 2 - absolute refractory period
   4. Phase 3 - relative refractory period, repolarization is very strong
   5. Phase 4 - repolarization finishes; cells return to resting potential
3. Major Cardiac Ions and Membrane Potentials [2,4,8]
   1. Calcium (Ca2+) - passive flux inward, current inward, depolarization
   2. Sodium (Na+) - passive flux inward, current inward, depolarization
   3. Potassium (K+) - passive flux outward, current outward, repolarization
   4. Chloride (Cl-) - passive flux inward, current outward (negative charge), repolarization
4. Depolarization [8]
   1. PHASE 0
   2. Sodium (Na+) and Ca2+ enter cell after threshold potential reached
   3. In atrial and ventricular tissue, and in His-Perkinje system, currently mainly due to Na+
   4. In SA and AV nodes, there is little or no Na+ current, and Ca2+ is major current
   5. Ca2+ are weak, and do not appear on electrocardiogram (ECG)
5. Refractoriness
   1. Period of recovery that cells require until next depolarization (PHASE 0)
   2. Corresponds to Na+ channel closure through h gate
6. Repolarization
   1. PHASE 3
   2. Occurs when outflow of K+ exceeds declining inflow of Na+ and Ca2+
   3. Three K+ currents have been identified: I(TO), I(Kr), I(KS)
   4. K+ initially exits cell through transient outward currents, I(TO)
   5. Most repolarization due to K+ flow through rapid outward rectifying channel, I(Kr)
   6. Additional repolarization due to K+ flow through slow outward rectifying channel, I(KS)
   7. Membrane potential becomes more negative, returning to to resting level
7. Automaticity
   [Figure] "Schematic of the A-V Node"
   1. Property of cardiac cell to depolarize spontaneously during PHASE 4 of action potential
   2. Sinoatrial (SA) node is major determinant here
   3. Ventricular focus can assume automaticity in absence of depolarizing voltage
   4. When a ventricular focus assumes firing rate, this is called ventricular escape
8. Threshold Potential
   1. PHASE 4 to 0
   2. Gradual (slow) entry of sodium into cell until rapid Na entry
9. Conduction - impulse propagation through cardiac tissues
10. Arrhythmia - abnormal automaticity or conduction of action potential in cardiac cell

B. Sodium (Na+) Channels [2]

1. Voltage Gated, Na+(V)
   1. Consists of alpha, beta, and beta1 subunits with six membrane spanning domains total
   2. Alpha subunit has 4 domains of 6-membrane alpha helices
   3. Therefore, only one alpha subunit is required for single channel formation
   4. Selectivity for Na+ >10 fold other ions
   5. Critical for normal cardiac and CNS functions
   6. Gating mechanisms are fairly well understood for Na+(V) channels
   7. Depending on gate conformation, Na+(V) exist in resting, active and inactive forms
2. Gating [11]
   1. Two major gates, m and h, have been described for Na+(V) channels
   2. The gates exist in different parts of the same (alpha) channel polypeptide
   3. Structural motifs responsible for gating m (rapid) and h (slow) gates understood
   4. There are three phsiologic conformations for these gates
   5. These conformations correspond exactly to the forms of Na+(V) channels
   6. In the resting, net closed state, the m gate is closed and h gate is open
   7. The m gate opens rapidly on depolarization from the resting state
   8. The h gate, open in the resting state, begins to close on depolarization
   9. The inactive (closed) state has the m gate open and the h gate closed
   10. The refractory period is due to the closure of the h gate
   11. As repolarization occurs, the m gate closes and the h gate slowly opens
3. Epithelial Na+ channels (amiloride sensitive)
   1. Non-voltage gated channels
   2. Found on apical membranes of many NaCl-absorbing epithelia
   3. Crucial for transepithelial salt trasport
   4. Blocked by the potassium sparing diuretic amiloride
   5. Bronchiolar epithelium and renal collecting duct contain major activities
   6. Renal channel is discussed below
   7. Bronchiolar channels can be blocked with amiloride, useful in cystic fibrosis
4. Na+ Channel (SCN5a) Abnormalities [2]
   1. Gain of function - Long QT Syndrome 3 (LQT3; see below)
   2. Loss of function: Progressive Conduction System (Lenegre's) disease
   3. Loss of function: Brugada Syndrome [14]
5. Na+ Channel blockers terminate arrhythmias by slowing cardiac conduction, prolonging refractoriness

C. Potassium (K+) Channels

1. Summary of K+ Channels [4,8]
   1. Inwardly (Anomolous) Rectifying (IR) K+ channel (Kir)
   2. Outward (Delayed) Rectifier (Ko): rapid (Kr) and slow (KS) forms
   3. Transient outward current (Ktr or K(TO))
   4. Calcium activated K+ channel
   5. Sodium activated K+ channel
   6. ATP sensitive K+ channels (Katp)
   7. Acetylcholine activated K+ channel
   8. Arachidonic acid-activated K+ channel
2. Voltage Gated (Kv)
   1. Simplest of voltage-gated channels
   2. Alpha subunit has six membrane spanning alpha helices
   3. Several different alpha subunits exist and can form homotetramers or heterodimers
   4. Four polypeptides are required for K+ channel
   5. ß-subunit is entirely cytosolic and alters voltage dependence of alpha subunits
3. Inwardly (Anomolous) Rectifying (IR) K+ Channel (Kir)
   1. Inward rectification means that inward flow of K+ is greater than outward flow at equal but opposite driving forces
   2. Some of the Kir channels are strongly rectifying, with little outward flow at all
   3. All have two-membrane spanning alpha helices with a loop between them
   4. IR caused by plugging internal mouth of channel
   5. Magnesium (Mg2+) is usual plugging molecule for weak IR channels
   6. Polyamines (spermine, spermidine, putrescine, cadaverine) and Mg2+ block strong IR
   7. Note that "normal" K+ ion flow is outward (see above), so this channel is "anomolous"
4. Outward (Delayed) Rectifying K+ Channel
   1. Channels open withen the heart is depolarized
   2. Carry the heart's major depolarizing current
   3. Heterogeneity in these channels contributes to variations in action potential durations
   4. Rapid and slow forms of the channels exist
   5. Kr (rapid) composed of gene products from HERG and KCNE2
   6. KS (slow) composed of gene prodcuts from KVLQT1 and KCNE1
5. ATP sensitive K+ channels (Katp)
   1. Found in pancreatic ß-cells, involved in insulin secretion
   2. Epithelial ATP-regulated secretory cheannel (Kir1, ROMK), found in kidney
   3. Also found in muscle, heart, CNS
   4. May be involved in protection from cell death during ischemia
   5. Weak inward rectification, inhibition by intracellular ATP
6. Pancreatic ß-Cell Katp Channel
   1. Formed by association of Kir6.2 subunits with SUR1, another Kir protein
   2. SUR1 is the sulfonylurea receptor and modulates channel function
   3. Stoichiometry of SUR1 to Kir6.2 is not presently known
   4. SUR1 is a member of the ABC (ATP binding cassette) family of proteins (see below)
   5. Sulfonylureas bind SUR1, inhibit the Katp channel, and stimulate insulin secretion
   6. SUR1 is mutated is familial persistent hyperinsulinemic hypoglycemia of infancy
7. Acetylcholine activated K+ channel (Kach)
   1. Vagal stimulation can hyperpolarize resting cardiac cells
   2. Mediated through acetylcholine receptors, activates Gi and opens Kach
   3. This slows muscle firing and reduces heart rate
   4. Similar transduction cascade occurs with adenosine binding to purinergic receptors
   5. Channel consists of heterodimer with two inwardly rectifying K+ channel proteins
8. Arachidonic acid-activated K+ channel (Kaa)
   1. Lipid activated potassium channels
   2. Fatty acids liberated in ischemic heart activate these receptors
   3. Result is shortened cardiac action potential due to more rapid repolarization
   4. Acidosis, which promotes K+ exit from cells, also shortens action potential
9. Long QT Syndromes [3,5,8]
   1. There are 6 well described congenital long QT syndromes, LQT1-6
   2. Previously known as Romano-Ward or Jervell and Lange-Nielsen Syndromes
   3. Jervell and Lange-Nielsen Syndrome is LQT1 with deafness
   4. Romano-Ward Syndrome is composed of LQT1, LQT2, and LQT3 genotypes
   5. Mutations in K+ channels which reduce outward K+ flow are most common
   6. Mutations in Na+ channel which increases Na+ inflow are also found (LQT3 only) [2]

D. Approach to Arrhythmias

1. Considerations
   1. Rate: Bradycardia versus Tachycardia versus Normal (for example, AV Dissociation)
   2. Origin: are there P waves? Atrial versus Ventricular versus Junctional Etiology
   3. Is the complex wide or narrow? All narrow complexes are supraventricular.
   4. Is the patient stable? Unstable patients are usually cardioverted emergently
   5. Is there a family history of the arrhythmia ? Is the patient young ? (suggests genetic)
2. Overview [6]
   [Figure] "Ventricular Arrhythmia Evaluation"
   1. Careful history with evaluation of prior events which might suggest arrhythmia
   2. Family history also important, as arrhythmias can have a genetic component
   3. Echocardiography is very important to evaluate cardiac structure
   4. Stress echocardiogram or nuclear study for patients with suspected ischemia
   5. Electrocardiogram (ECG) may identify at risk patients (long QTc, bundle branch blocks)
   6. Patients should be evaluated for coronary artery disease (CAD), cardiac ischemia
   7. Holter monitoring for patients with frequent events
   8. Cardiac event monitor for patients with infrequent events
   9. Ambulatory ECG monitoring with telephonic continuous loop monitors very helpful [7]
   10. Assess serum electrolyte levels, especially potassium, magnesium, and calcium
   11. Suggestions of arrhythmia may prompt physician to electrophysiologic testing (EPS)
3. Therapeutic Considerations
   1. Contributing factors such as drugs and/or ischemia should be addressed
   2. Most anti-arrhthymic agents increases the refractory period
   3. Also decrease rapid excitation of cardiac tissues
   4. Many reduce height (peak) of the action potential, which may reduce contractility (anti-inotropic)

E. Causes of Arrhythmias

1. Etiology of Tachyarrhythmias
   1. Reentry Mechanisms - impulse returns to originating area and "refeeds" circuit
   2. Ectopic Focus (automaticity) - "pacemaker cell"
   3. Triggered activity (polyfocal) - usually due to ischemia or hyperadrenergic conditions
2. Etiology of Bradyarrhythmias
   1. Resting Bradycardia - often normal variant, especially in young persons (high vagal tone)
   2. Conduction system disease
   3. Drug side effects
3. Ischemia
   1. Atherosclerosis with ischemia is likely major contributor to sudden cardiac death
   2. Ischemia is likely the most important contributor to acute ventricular arrhythmias
   3. Ischemia likely worsens any arrhythmia, either tachy- or bradycardias
   4. Patients with CAD, left ventricular dysfunction, and inducible VTach have higher risk of arrhythmic and overall death than patients with non-inducible VTach [11]
   5. Ischemia increases adenosine, fatty acid, and other release
   6. These compounds can influence the ion channel properties in the heart
   7. Sleep disorders - apnea/hypopnea
4. Sleep Apnea [10]
   1. Nocturnal Dysrhythmias most common
   2. Ventricular arrhythmias and sudden death ~4X increased risk with sleep apnea
5. Electrolyte Abnormalities
   1. Hyperkalemia: VF, atrial and ventricular tachycardias (VTach), heart block
   2. Hypokalemia: bradycardia, asystole, enhance digoxin toxicity, Torsade de Pointes, VFib
   3. Hypomagnesemia: Torsade de Pointes, enhance effects of other contributors
   4. Hypercalcemia: Tachycardias
6. Focus of abnormal activity
   1. Congenital Abnormalities
   2. Post-MI - high risk in low EF patients
   3. Pre-existing arrhythmias - Frequency of PVCs can help predict
   4. Genetic Syndromes
7. Genetic Syndromes (see above)
   1. Hypertrophic, dilated and restrictive cardiomyopathies
   2. Familial Atrial Fibrillation: mapped to chrom 10q22-24
   3. Other Arrhythmic Genetic Syndromes
8. Drugs
   1. Digitalis
   2. Antiarrhythmic Agents
   3. Tricyclic Antidepressants: Prolonged QT Interval and widened QRS interval
   4. Neuroleptic Agents (phenothiazines, butyrphenones): prolonged QT
   5. Anti-histamines: terfenadine and astemizole prolong QTc, associated with Torsades
   6. Cisapride (Propulsid®): prolonged QTc associated with Torsades
   7. QTc prolongation by cisapride and anti-histamines exacerbated by mycins (such as erythromycin) and azoles (ketoconazole, fluconazole and itraconazole)
   8. This exacerbation due to inhibition of drug metabolizing enzymes (CYP 3A4)
9. Digitalis (digoxin, Lanoxin®)
   1. Decreases rate of AV Node Conduction
   2. Proarrhythmic in many settings:
   3. AV Block with PVCs most common (Ventricular Bigeminy especially common)
   4. May cause any arrhythmia except atrial flutter (atrial fibrillation is very rare)
   5. Potentiated by: ischemia, low K,low Mg; high Ca, Hypothyroidism
   6. Digitalis should not be used in patients with amyloidosis (high risk of VTach or VF)
10. Antiarrhythmic Agents
    1. Prolongation of QT Interval (Type IA agents,Sotalol) may cause Torsades de Pointes
    2. Sudden cardiac death - Type 1C (flecainide, encainide) in ischemic patients
    3. Increased overall mortality seen with quinidine (may be arrhythmias) [13]

F. Torsade de Pointes (TDP) [3]

1. Means "Twisting of the points"
2. Polyfocal ventricular tachycardia
3. Contributors
   1. Electrolyte abnormalities - paricularly hypomagnesemia and hypocalcemia
   2. Drugs which prolong the QTc interval [5]
   3. Azoles and macrolide antibiotics can exacerbate QTc prolongation by other drugs
   4. Female gender is a risk factor for TDP associated with drugs [5]
   5. Congenital diseases of QT prolongation, "Long QT Syndromes" (see above)
4. Drug Classes Prolonging QT Interval [5]
   1. Types IA and IB and III Anti-Arrhythmic Agents
   2. Most typical neuroleptics prolong QTc interval; phenothiazines particularly problematic
   3. Tricyclic Antidepressants [5]
   4. Methadone doses >60mg/d
   5. Cisapride (Propulsid®) - very low risk, but drug has been withdrawn from market [4]
   6. Antihistamines (H1-Blockers): terfenadine and astemizole both withdrawn from market
5. Drugs Contributing to QT Prolongation
   1. Macrolides: erythromycin, clarithromycin, troleandomycin
   2. Quinolones: moxifloxacin (Avelox®), grepafloxacin, sparfloxacin
   3. Azole antifungals - ketoconazole, fluconazole and others
   4. Digitalis toxicity
   5. Arsenic trioxide - treatment for acute promyelocytic leukemia [6]
   6. Ritonavir
   7. In most cases, these "contributing" agents inhibit P450 metabolic enzymes
   8. Effects usually due to binding to ion channels in cardiac tissue
   9. HERG (inward rectifying K+ channels) most often implicated
6. Treatment of TDP
   1. Administer high dose magnesium
   2. Consider administration of calcium (which will shorten QTc)
   3. Increase heart rate - pharmacologically or with pacemaker
   4. Stop offending agent

G. Anti-Arrhythmic Agent Classes

1. Class I: Fast Sodium Channel Blockers
   1. IA: Procainamide, Quinidine, Disopyramide
   2. IB: Lidocaine, Mexilitine
   3. IC: Flecainide, Encainide, Propafenone
2. Class II: ß-Adrenergic Blocking Agents
3. Class III: Agents with Mixed Activity (Atypical Agents)
   1. Sotalol
   2. Amiodarone
4. Class IV: Calcium Channel Blockers

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