The Arrhythmias

THE ARRHYTHMIAS

Ibrahim Sales, Pharm.D.Assistant Professor of Clinical Pharmacy

King Saud [email protected]

Key Concepts• Use of antiarrhythmic drugs in the US has declined due to

major trials showing increased mortality associated with use • recognition of proarrhythmia as significant adverse effect• advancements in nondrug therapy technology

• ablation • implantable cardioverter-defibrillator (ICD)

• Antiarrhythmic medications frequently cause adverse effects, complex pharmacokinetics

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Normal Conduction• Electrical activity initiated at sinoatrial (SA) node

• highest rate of spontaneous impulse generation• Moves through cardiac tissue to ventricles at the

atrioventricular (AV) node• Flows down bundle of His to bundle branches & the

Purkinje system• 2 bundle branches on left; 1 on the right

• Impulse reaches refractory tissue (recently excited) & dies out • SA node recovers & fires again

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http://youtu.be/te_SY3MeWys

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Normal Conduction of the Heart• Inherent HR• SA node

• 60-100 bpm

• AV JUNCTION• 40-60bpm

• VENTRICULAR • 20-40 bpm

Normal Conduction• Phase 0: initial, rapid depolarization of atrial & ventricular

tissues; increase in cell Na+ permeability; Na+ influx; rapid depolarization overshoots electrical potential, brief period of repolarization

• Phase 1: transient active K+ efflux; Ca2+ influx • Phase 2: Ca2+ influx balanced by K+ efflux; plateau• Phase 3: membrane permeable to K+ efflux; repolarization• Phase 4: gradual depolarization; constant Na+ leak to

intracellular space balanced by K+ efflux

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Abnormal Conduction• Tachyarrhythmia: 2 categories

• abnormal impulse generation • “automatic” tachycardia

• abnormal impulse conduction • “reentrant” tachycardia

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Reentrant Tachycardias

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Three conditions required: • two pathways for impulse

conduction• an area of unidirectional block

(prolonged refractoriness) in one of these pathways

• slow conduction in the other pathway

Antiarrhythmic Drugs• Vaughan Williams classification limitations

• incomplete, does not include digoxin, adenosine• many agents have properties of more than 1 class • does not incorporate mechanism of tachycardia

termination/prevention, clinical indications, side effects• agents “labeled” within a class

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Classification of Antiarrhythmic DrugsType Drug Conduction

Velocitya Refractory Period Automaticity Ion Block

Ia Quinidine ↓ ↑ ↓ Sodium (intermediate)

Procainamide PotassiumDisopyramide

Ib Lidocaine 0/ ↓ ↓ ↓ Sodium (fast on-off)Mexiletine

Ic Flecainide ↓ ↓ 0 ↓ Sodium (slow on-off)Propafenoneb Potassiumd

Moricizinec

IIe β-blockers ↓ ↑ ↓ Calcium (indirect)III Amiodaronef 0

↑↑

0

Potassium

DofetilideSotalolb

IbutilideIVe Verapamil ↓ ↑ ↓ Calcium

Diltiazem

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aVariables for normal tissue models in ventricular tissue. bAlso has type II, β-blocking actions. cClassification controversial. d Not clinically manifest. eVariables for SA & AV nodal tissue only. fAlso has sodium, calcium, β-blocking actions

DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th Edition: http://www.accesspharmacy.com

Antiarrhythmic MedicationsVaughan-Williams Classification

Mechanism of Action

Drugs Indication

Ia Na+ channel block (intermediate association and dissociation)

QuinidineProcainamideDisopyramide

Atrial fib, Wolff-Parkinson-White syndrome, premature ventricular contractions, ventricular tachycardia**Paroxysmal supraventricular tachycardia-Disopyramide only

Ib Na+ channel block (fast association and dissociation)

LidocaineMexiletineTocainide

Ventricular arrhythmias only: Premature ventricular contractionsVentricular tachycardiaVentricular fibrillation

Ic Na+ channel block (slow association and dissociation)

Propafenone (class II activity)Flecainide

Propafenone: Atrial fib, paroxysmal supraventricular tachycardia, life-threatening ventricular arrhythmias Flecainide: Atrial fib, paroxysmal supraventricular tachycardia, life-threatening ventricular arrhythmias, Wolff-Parkinson-White syndrome

II Β-block (indirect Ca2+ block)

β-blockers (i.e. metoprolol)

Atrial fib, atrial flutter, paroxysmal supraventricular tachycardia

III Primarily K+ channel block

Amiodarone (class Ib, II, IV activity)Sotalol (class II activity)DofetilideIbutilideDronedarone (class Ib, II, IV activity)

Wolff-Parkinson-White syndromeTreatment of Atrial fib and flutter*Sotalol: Maintenance only*Ibutilide: Conversion onlyAmiodarone or sotalol: Treatment and maintenance of life-threatening ventricular arrhythmias

IV Ca2+ channel block DiltiazemVerapamil

Atrial fib, Atrial flutter, paroxysmal supraventricular tachycardia

Additional agents

Direct nodal block; increases vagal activity

Digoxin Atrial fib

Direct nodal block Adenosine Termination of AV nodal-dependent supraventricular tachycardias (AV nodal reentrant tachycardia)Contraindicated in ventricular tachycardias

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0 mV

AADs Have distinct Characteristics depending on which ion channels they block

Class II: Beta Blockers

Class III: amiodarone, dofetilide, dronedarone, sotalol, ibulitide

Class I: quinidine, procainamide, dispopyramide, lidocaineFlecainidepropafenone

K+

Ca+

Ca+

Na+

Class I

Class IV

Class III

Class II

-90mV

Class IV: CCB

Type I Agents• Block Na+ conduction: “plug up” channels• Channel state affinity

• lidocaine, flecainide: block during inactivated state• quinidine: binds when channel is open/activated

• Binding & unbinding specific to the receptor • Type Ia: intermediate binding kinetics• Type Ib: fast receptor binding/dissociation• Type Ic: slow receptor binding/dissociation

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Type Ia Antiarrhythmics• Quinidine, procainamide, disopyramide• Slow conduction velocity, prolong refractoriness, decrease

automatic properties of Na+ dependent conduction tissue • reentry: transform area of unidirectional block into bidirectional

block • wave cannot get through pathway in retrograde fashion • area still refractory

• Primarily Na+ channel blockers• some effects attributed to K+ channel blockade• used for supraventricular & ventricular arrhythmias

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Type Ib Antiarrhythmics

• Lidocaine, mexiletine: weak Na+ channel antagonists

• Shorten refractoriness without affecting conduction velocity; improve antegrade conduction & eliminate unidirectional block

• Used primarily in ventricular arrhythmias

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Type Ib Antiarrhythmics

• Lidocaine• Indicated for Pulseless VT/VF conversion or VT with a pulse. VT

maintenance• PK: Reduce dose in those with HF, liver disease, low body weight and

renal dysfunction and in the elderly• DI: Amiodarone (increased lidocaine levels)

• Mexiletine• VT maintenance

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Type Ic Antiarrhythmics

• Propafenone, flecainide• Profoundly slow conduction velocity• Refractoriness relatively unaltered • Eliminate reentry: slow conduction to point where

impulse is extinguished & cannot propagate • Potent Na+ blockers• Effective for both ventricular & supraventricular arrhythmias

• ventricular arrhythmia use limited by proarrhythmia risk

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Type Ic Antiarrhythmics• Propafenone, Flecainide

• Indicated for patients with AF without structural heart disease. • Avoid in patients with LV dysfunction and/or CAD. • Can be initiated in an outpatient setting for patients with

paroxysmal atrial fibrillation and no associated structural heart disease

• Follow-up: • frequent ECG monitoring or via transtelephonic monitoring for potential

signs of proarrhythmia.

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Type Ic Antiarrhythmics

Type II Agents• β-blockers• Antiarrythmic mechanism: anti-adrenergic actions

• SA & AV nodes influenced by adrenergic innervation• Adrenergic stimulation increases conduction velocity,

shortens refractoriness & increases automaticity of nodal tissues• β-blockers antagonize these effects• useful for exercise related tachycardias or other tachycardias

induced by high sympathetic tone

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Non-Acute Setting and Chronic Maintenance Rate Control Therapy of Atrial FibrillationDrug Loading Dose (Oral) Onset Maintenance Dose (Oral) Major Adverse Effects

Rate Control

Metoprolol Same as maintenance 4-6 hours 25-100mg BID Hypotension, bradycardia, HF and asthma exacerbation, heart block

Propanolol Same as maintenance 60-90 minutes 80-240mg in divided doses

Hypotension, bradycardia, HF and asthma exacerbation, heart block

Diltiazem Same as maintenance 2-4 hours 120-360mg daily in divided doses; slow release available

Hypotension, HF exacerbation, heart block

Verapamil Same as maintenance 1-2 hours 120-360mg daily in divided doses; slow release available

Hypotension, HF exacerbation, heart block

Rate control in patients with heart failure and without accessory pathway

Digoxin 0.5mg daily 2 days 0.125-0.375mg daily Cardiac arrhythmias, headache, vision disturbances, nausea, vomiting, diarrhea

Amiodarone 800mg daily x 1 week600mg for 1 week400mg for 4-6 weeks

1-3 weeks 200mg daily Pulmonary fibrosis, hypothyroidism, hepatotoxicity, neurologic toxicity, TdP, AV block

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Type III Agents• Amiodarone, sotalol, ibutilide, dofetilide

• Prolong refractoriness in atrial & ventricular tissue

• Delay repolarization: block K+ channels

• Danger of blocking K+ channel too much: causes arrhythmias such as Torsades de Pointes (TdP)

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Type III Agents• Amiodarone & sotalol: effective in most supraventicular &

ventricular tachycardias

• Sotalol inhibits outward K+ movement during repolarization; nonselective β-blocking actions• Hospitalization mandatory for initiation, • obtain QT 2–3 hours after first 5 doses, may increase dose after 3

days; NTE QT > 500 milliseconds• Not effective for AF conversion

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Case 1A 52-year-old man comes into the clinic with a medical history significant for atrial fibrillation, diabetes, and hypertension. Current medications include metoprolol tartrate 100 mg twice daily, glyburide 10 mg twice daily, lisinopril 40 mg/day, and hydrochlorothiazide 25 mg/day. He comes to the clinic today with shortness of breath and fatigue. An ECG shows that he is in atrial fibrillation. The physician would like to admit the patient and start dofetilide.

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Case 1Which one of the following medications should be discontinued before dofetilide is initiated? A. Glyburide.B. Metoprolol.C. Hydrochlorothiazide.D. Lisinopril.

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Type III Agents• Dofetilide (oral only) & ibutilide (IV only)

• used for acute conversion of AF or atrial flutter to sinus rhythm

• block rapid component of the delayed K+ rectifier current • Dofetilide can be used to maintain sinus rhythm after

conversion• Ibutilide requires ECG monitoring during and 4 hours after infusion

• DIs: CYP 3A4 inhibitors or drugs secreted by the kidney (ketoconazole, verapamil, trimethoprim, megestrol); HCTZ should be d/c’d as concentrations of dofetilide increase (hypokalemia, hypomagnesemia, increases the concentration of dofetilide inhibition of renal tubular secretion)

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Case 1A 52-year-old man comes into the clinic with a medical history significant for atrial fibrillation, diabetes, and hypertension. Current medications include metoprolol tartrate 100 mg twice daily, glyburide 10 mg twice daily, lisinopril 40 mg/day, and hydrochlorothiazide 25 mg/day. He comes to the clinic today with shortness of breath and fatigue. An ECG shows that he is in atrial fibrillation. The physician would like to admit the patient and start dofetilide.

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Case 1Which one of the following medications should be discontinued before dofetilide is initiated? A. Glyburide.B. Metoprolol.C. Hydrochlorothiazide.D. Lisinopril.

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Case 2For a 42-year-old man with atrial fibrillation who did not respond to class Ic agents, the electrophysiologist started dofetilide 500 mcg twice daily in the hospital 2 weeks ago. He comes to the clinic today for a follow-up. An ECG was done today showing normal sinus rhythm and QTc of 0.455 seconds (baseline QTc 0.395 seconds). The only medication change was the initiation of azithromycin yesterday for bacterial sinusitis.

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Case 2Because this drug was initiated, which one of the following changes needs to take place and why? A.Discontinue azithromycin, administer an alternative antibiotic, and have patient return in 2 days for repeat ECG. B.Finish course of azithromycin, decrease dose of dofetilide to 125 mcg twice daily, and have patient return in 3–7 days for repeat ECG. C.Finish course of azithromycin, continue current dose of dofetilide at 500 mcg twice daily, and have patient return in 2 days for repeat ECG to reevaluate. D.Withdraw dofetilide and return to clinic in 3–7 days for repeat ECG.

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Dofetilide Dosing• AF conversion:

• 500mcg PO twice daily (CrCl>60mL/min)• 250mcg PO twice daily (CrCl 40-60mL/min)• 125mcg PO twice daily (20-40mL/min)• Contraindicated CrCl<20mL/min

• AF maintenance: Titrate down on the basis of QTc• Must be started inpatient. Determine QTc 2-3 hours

after initial dose. If QTc increases by>15% or >0.5 sec, reduce dose by half.

• Need a 3-month washout period if initiated after amiodarone failure

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Case 2For a 42-year-old man with atrial fibrillation who did not respond to class Ic agents, the electrophysiologist started dofetilide 500 mcg twice daily in the hospital 2 weeks ago. He comes to the clinic today for a follow-up. An ECG was done today showing normal sinus rhythm and QTc of 0.455 seconds (baseline QTc 0.395 seconds). The only medication change was the initiation of azithromycin yesterday for bacterial sinusitis.

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Case 2Because this drug was initiated, which one of the following changes needs to take place and why? A.Discontinue azithromycin, administer an alternative antibiotic, and have patient return in 2 days for repeat ECG. B.Finish course of azithromycin, decrease dose of dofetilide to 125 mcg twice daily, and have patient return in 3–7 days for repeat ECG. C.Finish course of azithromycin, continue current dose of dofetilide at 500 mcg twice daily, and have patient return in 2 days for repeat ECG to reevaluate. D.Withdraw dofetilide and return to clinic in 3–7 days for repeat ECG.

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Case 3A 65-year-old man was admitted to the hospital after several shocks from his implantable cardiac defibrillator (ICD) caused by episodes of ventricular tachycardia (VT). He was placed on amiodarone during his admission and was discharged on 400 mg/day. He presents to the clinic two weeks later for a follow-up. You evaluate his chart to make sure that baseline monitoring has been done. You find that he had a thyroid panel and chest radiograph performed while an inpatient.

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Case 3Which one of the following laboratory/baseline monitoring parameters also needs to be obtained because amiodarone is being initiated?A. LFTs.B. CBC.C. Lipid panel. D. Electrolytes.

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Amiodarone• Characteristics of all Vaughan Williams classes

• Na+ channel blocker with fast on/off kinetics• noncompetitive, nonselective β-blocker actions• blocks K+ channels• small degree of Ca2+ antagonist activity

• Quick onset with IV administration• Initial action: β-blockade• Predominant effect with chronic use: prolongation of

repolarization• Low proarrhythmic potential

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Time Course & Electrophysiologic Effects of AmiodaroneClass Mechanis

mEP ECG IV Oral

Min-hrs

Hrs-days

Days-wks

Wks-month

sType I Na+ block ↑HV ↑QR

S0 + + ++

Type II β-block ↑ AH ↑ PR, ↓ HR

++ ++ ++ ++

Type III

K+ block ↑VERP, ↑AERP

↑ QT 0 + ++ ++++

Type IV

Ca2+ blocka ↑ AH ↑ PR + + + +

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aRate-dependent.AERP, atrial effective refractory period; AH, atria-His interval; ECG, electrocardiographic effects; EP, electrophysiologic actions; HR, heart rate; HV, His-ventricle interval; VERP, ventricular effective refractory period.


Amiodarone• Most commonly prescribed antiarrhythmic • Used in chronic & acute supraventricular/ventricular

arrhythmias• Unusual pharmacologic effects, pharmacokinetics, dosing,

adverse effects• extremely long t½ (15 to 100 days)• large volume of distribution (Vd)• inhibits P-glycoprotein & most CYP-P450 enzymes

• many drug interactions• severe multi-organ toxicities with chronic use

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Amiodarone Dosing• AF conversion

• IV: 5-7mg/kg IV over 30-60min.; then 1.2-1.8g/day; continue IV or divided doses until 10g total

• PO (inpatient): 1.2-1.8g/day in divided doses until 10g total• PO (outpatient) 400mg/day x 2-4 weeks

• AF maintenance• 100-400mg/day

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Side Effect Monitoring Side Effect Management

Pulmonary fibrosis Chest radiograph (baseline, then every 12 months), pulmonary function tests

Discontinue amiodarone immediately and initiate corticosteroid therapy

Hypothyroidism Thyroid function tests (baseline, then q6 months)

Thyroid hormone supplementation

Hyperthyroidsim Thyroid function tests (baseline, then q6 months)

Antithyroid drugs

Optic neuritis/neuropathy Ophthalmologic exam (baseline, then q12months)

Discontinue amiodarone

Corneal microdeposits Slit-lamp exam (routine monitoring not necessary)

No treatment necessary

Increased liver function tests (LFTs)

LFTs (baseline, then q6months) Consider lowering the dose or discontinuing drug if LFTs > 3x normal

Bradycardia/heart block ECG (baseline, then q3-6months)

Lower the dose, if possible, or discontinue amiodarone if severe

Tremors, ataxia, peripheral neuropathy

History/physical examination (each office visit)

Lower the dose, if possible, or discontinue drug if severe

Photosensitivity/blue-gray skin discoloration

History/physical examination(each office visit)

Advise patient to wear sunblock outside

40Amiodarone Monitoring


Case 3A 65-year-old man was admitted to the hospital after several shocks from his implantable cardiac defibrillator (ICD) caused by episodes of ventricular tachycardia (VT). He was placed on amiodarone during his admission and was discharged on 400 mg/day. He presents to the clinic two weeks later for a follow-up. You evaluate his chart to make sure that baseline monitoring has been done. You find that he had a thyroid panel and chest radiograph performed while an inpatient.

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Case 3Which one of the following laboratory/baseline monitoring parameters also needs to be obtained because amiodarone is being initiated?A. LFTs.B. CBC.C. Lipid panel. D. Electrolytes.

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Type IV Agents

• Dihydropyridine CCBs: • no significant antiarrhythmic effects

• Non-dihydropyridine CCBs: • verapamil, diltiazem• block L-type Ca2+ channels • slow conduction, prolong refractoriness • ↓ SA/AV node automaticity

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Type IV Agents• Non-dihydropyridine CCBs:

• effective for SA/AV node automatic or reentrant tachycardias

• slow AV conduction• help exercise induced tachycardias • benefits for tachycardias caused by triggered automaticity

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Case 4An 82-year-old woman with a medical history of atrial flutter, heart failure New York Heart Association (NYHA) functional class III (continually in and out of the hospital for exacerbation), and hypertension. The last time this patient was seen in the clinic, the decision was made for the patient to undergo ablation of atrial flutter. The patient cancelled the procedure because her family did not believe it was a good idea. The physician would like to initiate dronedarone.

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Case 4Which one of the following statements would explain why you disagree with the use of dronedarone in this patient? A. Dronedarone should not be considered

an option for this patient because it is not approved for the treatment of atrial flutter.

B. Dronedarone should not be considered an option for this patient because the patient has hypertension.

C. Dronedarone should not be consideredan option for this patient because she has NYHA functional class III heart failure and frequent exacerbation.

D. Dronedarone should not be considered an option for this patient because it is better used in patients with NYHA functional class IV.

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Dronedarone• MOA: Na+, K+, Ca2+ channel blocker, β-blocker• PK: Half-life 13-19 hours• CIs: QTc≥0.5 sec or PR≥0.28 sec, HF NYHA IV or

recent HF exacerbation NYHA class II-III, severe hepatic impairment, second- or third-degree heart block, heart rate < 50 beats/min

• DIs: CYP3A4 inhibitors, QT-prolonging agents, P-glycoprotein substrates• Decrease dose of digoxin by 50%• Monitor for myopathy with statins

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Dronedarone• Dosing:

• AF conversion/AF maintenance:• 400mg PO twice daily• Food helps increase absorption

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Case 4An 82-year-old woman with a medical history of atrial flutter, heart failure New York Heart Association (NYHA) functional class III (continually in and out of the hospital for exacerbation), and hypertension. The last time this patient was seen in the clinic, the decision was made for the patient to undergo ablation of atrial flutter. The patient cancelled the procedure because her family did not believe it was a good idea. The physician would like to initiate dronedarone.

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Case 4Which one of the following statements would explain why you disagree with the use of dronedarone in this patient? A. Dronedarone should not be considered

an option for this patient because it is not approved for the treatment of atrial flutter.

B. Dronedarone should not be considered an option for this patient because the patient has hypertension.

C. Dronedarone should not be consideredan option for this patient because she has NYHA functional class III heart failure and frequent exacerbation.

D. Dronedarone should not be considered an option for this patient because it is better used in patients with NYHA functional class IV.

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DronedaroneThe U.S. Food and Drug Administration (FDA) has completed a safety review of the heart drug Multaq (dronedarone). This review showed that Multaq increased the risk of serious cardiovascular events, including death, when used by patients in permanent atrial fibrillation (AF). The review was based on data from two clinical trials, the PALLAS trial (Permanent Atrial FibriLLAtion Outcome Study Using Dronedarone on Top of Standard Therapy) and the ATHENA trial (which supported Multaq's approval for treatment of non-permanent AF). FDA is providing new information and recommendations for the use of Multaq to manage the potential serious cardiovascular risks with the drug.

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DronedaroneThe Multaq drug label has been revised with the following changes and recommendations:Healthcare professionals should not prescribe Multaq to patients with

AF who cannot or will not be converted into normal sinus rhythm (permanent AF), because Multaq doubles the rate of cardiovascular death, stroke, and heart failure in such patients.

Healthcare professionals should monitor heart (cardiac) rhythm by electrocardiogram (ECG) at least once every 3 months. If the patient is in AF, Multaq should be stopped or, if clinically indicated, the patient should be cardioverted.

Multaq is indicated to reduce hospitalization for AF in patients in sinus rhythm with a history of non-permanent AF (known as paroxysmal or persistent AF)

Patients prescribed Multaq should receive appropriate antithrombotic therapy.

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DronedaroneMultaq improves CV outcomes in some patients with paroxysmal or

persistent atrial fib. These resolve spontaneously or with cardioversion.

New evidence suggests that patients on Multaq for permanent atrial fib actually have a higher risk of death and cardiovascular events.

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Adverse EffectsQuinidine Cinchonism, diarrhea, abdominal cramps, nausea, vomiting,

hypotension, TdP, aggravation of underlying HF, conduction disturbances or ventricular arrhythmias, fever, hepatitis, thrombocytopenia, hemolytic anemia

Procainamide Systemic lupus erythematosus, diarrhea, nausea, vomiting, TdP, aggravation of underlying HF, conduction disturbances or ventricular arrhythmias, agranulocytosis

Disopyramide Anticholinergic symptoms (dry mouth, urinary retention, constipation, blurred vision), nausea, anorexia, TdP, HF, aggravation of underlying conduction disturbances and/or ventricular arrhythmias

Lidocaine Dizziness, sedation, slurred speech, blurred vision, paresthesia, muscle twitching, confusion, nausea, vomiting, seizures, psychosis, sinus arrest, aggravation of underlying conduction disturbances

Mexiletine Dizziness, sedation, anxiety, confusion, paresthesia, tremor, ataxia, blurred vision, nausea, vomiting, anorexia, aggravation of underlying conduction disturbances or ventricular arrhythmias

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Adverse Effects

Flecainide Blurred vision, dizziness, dyspnea, headache, tremor, nausea, aggravation of underlying HF, conduction disturbances or ventricular arrhythmias

Propafenone

Dizziness, fatigue, bronchospasm, headache, taste disturbances, nausea, vomiting, bradycardia or AV block, aggravation of underlying HF, conduction disturbances or ventricular arrhythmias

Amiodarone

Tremor, ataxia, paresthesia, insomnia, corneal microdeposits, optic neuropathy/neuritis, nausea, vomiting, anorexia, constipation, TdP (< 1%), bradycardia or AV block (IV and oral use), pulmonary fibrosis, liver function test abnormalities, hepatitis, hypothyroidism, hyperthyroidism, photosensitivity, blue-gray skin discoloration, hypotension (IV use), phlebitis (IV use)

Dofetilide Headache, dizziness, TdPIbutilide Headache, TdP, hypotensionSotalol Dizziness, weakness, fatigue, nausea, vomiting, diarrhea,

bradycardia, TdP, bronchospasm, aggravation of underlying HF

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THE ARRHYTHMIAS

Ibrahim Sales, Pharm.D.Assistant Professor of Clinical Pharmacy

King Saud [email protected]

The Arrhythmias

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