EVALUATION OF ANTIARRHYTHMIC DRUGS

Dr. Nitin Shinde1st Year ResidentLTMMC & GH, Mumbai - 22DATE- 22-02-2014.

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CONTENTS

Introduction- Basic Understanding of Arrhythmia & ECG. Classification Of Drugs

Genetical methods. Clinical evaluation. Conclusion.

In – Vitro methods:

1) Isolated guinea pig papillary

muscle.

2) Langendorff technique

3) Acetylcholine & potassium

Induced arrhythmia

In-Vivo Methods:

Chemically induced

arrhythmia

Electrically induced

arrhythmia

Mechanically induced

arrhythmia

Exercise Induced Arrhythmia

SA NODE FIRES AT 60-100 BEATS/SEC

SPREADS THROUGH ATRIA

ENTERS THE AV NODE(DELAY OF 0.15 SEC)

PROPAGATES THROUGH HIS PURKINJE SYSTEM

DEPOLARIZES VENTRICLES BEGINNING FROM ENDOCARDIAL SURFACE OF APEX TO EPICARDIAL SURFACE OF BASE

Normal Sinus Rhythm

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The Resting Membrane Potential of the cell is -95mV

This ionic gradient is maintained by

Active mechanisms like the Na+ pump and

Na+/K+ ATPase (Electrogenic)

Fixed anionic charges within the cell

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Phase 0:RapidDepolarisation

(Na+ influx)

Phase 1:Early

Repolarisation(Inward Na+ current

deactivated,Outflow of K+):

Transient Outward Current

Phase 2:Plateau Phase

(Slow inward Ca2+ Current balanced by outward delayed rectifier K+

Current)Phase 3:

Late Repolarisation(Ca 2+current inactivates,K+ outflow)

Action Potential of Cardiac Muscle

REGULATION BY AUTONOMIC TONEParasympathetic/Vagus Nerve stimulation:

• Ach binds to M receptors, releasing G protein βγ subunits

• Activate Ach dependent K+ current

• ↓ slope of Phase 4

Sympathetic stimulation:

• Activation of β1 receptors

• Augmentation of L-type Ca2+ current and funny currents

• ↑ slope of Phase 4

Cardiac Arrhythmias

Arrhythmia means an Abnormal heart rhythm

Results from the abnormalities of:

Impulse generation (Rate or Site of origin)

Conduction Both

CLASSIFICATION OF ARRHYTHMIAS1. Characteristics:

a. Flutter – very rapid but regular contractionsb. Tachyarrhthmia – increased ratec. Bradyarrhythmia – decreased rated. Fibrillation – disorganized contractile activity

2. Sites involved:

a. Ventricularb. Atrialc. SA Noded. AV Node

Supraventricular

MECHANISMS OF CARDIAC ARRHYTHMIAS

(A) Enhanced Automaticity:

In cells which normally display spontaneous diastolic depolarization (SA Node, AV Node, His-Purkinje System)

Automatic behavior in sites that ordinarily lack pacemaker activity

A normal cardiac action potential may be interrupted or followed by an abnormal depolarization

Reaches threshold & causes secondary upstrokes

2 Major forms:

1. Early Afterdepolarization2. Late Afterdepolarization

(B) Afterdepolarization and Triggered Automaticity

(C) Re-entrant Arrhythmia

Defined as circulation of an activation wave around an inexitable object

3 requirements for Re-entrant Arrhythmia:

1. Obstacle to conduction

2. Unidirectional block

3. CT>ERP

Unidirectional Block

Establishment of Re-entrant circuit

NORMAL ECG :  P wave – Atrial depolarisation. QRS wave – ventricular depolarisation. T wave – ventricular repolarisation.

Management Of

Arrhythmias

MANAGEMENT

Acute Management Prophylaxis

Non Pharmacological Pharmacological

NON PHARMACOLOGICAL

Acute1. Vagal Maneuvers2. DC Cardioversion

Prophylaxis1. Radiofrequency Ablation2. Implantable Defibrillator

Pacing (Temporary/ Permanent)

PHARMACOLOGICAL APPROACH

Drugs may be antiarrhythmic by:

Suppressing the initiator mechanism Altering the re-entrant circuit

1. Terminate an ongoing arrhythmia2. Prevent an arrhythmia

VAUGHAN WILLIAMS CLASSIFICATION

Phase 4

Phase 0

Phase 1

Phase 2

Phase 3

0 mV

-80mV

II

IIII

IV

Class I: block Na+ channels Ia (quinidine, procainamide, disopyramide) (1-10s)Ib (lignocaine) (<1s)Ic (flecainide) (>10s)

Class II: ß-adrenoceptor antagonists (atenolol, sotalol)

Class III: block K+ channels (amiodarone, dofetilide,sotalol)

Class IV: Ca2+ channel antagonists (verapamil, diltiazem)

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CLASSIFICATION OF ANTIARRHYTHMICS(BASED ON MECHANISMS OF ACTION)

Class I – blocker’s of fast Na+ channels Subclass IA

Cause moderate Phase 0 depression Prolong repolarization Increased duration of action potential Includes

Quinidine – 1st antiarrhythmic used, treat both atrial and ventricular arrhythmias, increases refractory period

Procainamide - increases refractory period but side effects Disopyramide – extended duration of action, used only for

treating ventricular arrthymias

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CLASSIFICATION OF ANTIARRHYTHMICS(BASED ON MECHANISMS OF ACTION)

Subclass IB Weak phase 0 depression Shortened depolarization Decreased action potential duration Includes

Lidocane (also acts as local anesthetic) – blocks na+ channels mostly in ventricular cells, also good for digitalis-associated arrhythmias

Mexiletine - oral lidocaine derivative, similar activity Phenytoin – anticonvulsant that also works as antiarrhythmic

similar to lidocane

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CLASSIFICATION OF ANTIARRHYTHMICS(BASED ON MECHANISMS OF ACTION)

Subclass IC Strong Phase 0 depression No effect of depolarization No effect on action potential duration

Includes Flecainide (initially developed as a local anesthetic)

Slows conduction in all parts of heart, Also inhibits abnormal automaticity

Propafenone Also slows conduction Weak β – blocker Also some Ca2+ channel blockade

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CLASSIFICATION OF ANTIARRHYTHMICS(BASED ON MECHANISMS OF ACTION) Class II – β–adrenergic blockers

Based on two major actions1) blockade of myocardial β–adrenergic receptors2) Direct membrane-stabilizing effects related to Na+ channel blockade

Includes Propranolol

causes both myocardial β–adrenergic blockade and membrane-stabilizing effects

Slows SA node and ectopic pacemaking Can block arrhythmias induced by exercise or apprehension Other β–adrenergic blockers have similar therapeutic effect

Metoprolol Nadolol Atenolol Acebutolol Pindolol Stalol Timolol Esmolol

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CLASSIFICATION OF ANTIARRHYTHMICS(BASED ON MECHANISMS OF ACTION)

Class III – K+ channel blockers Developed because some patients negatively

sensitive to na channel blockers (they died!) Cause delay in repolarization and prolonged

refractory period Includes

Amiodarone – Prolongs action potential by delaying K+ efflux but many other effects characteristic of other classes

Ibutilide – slows inward movement of na+ in addition to delaying K + influx.

Bretylium – First developed to treat hypertension but found to also suppress ventricular fibrillation associated with myocardial infarction

Dofetilide - Prolongs action potential by delaying K+ efflux with no other effects

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CLASSIFICATION OF ANTIARRHYTHMICS(BASED ON MECHANISMS OF ACTION)

Class IV – Ca2+ channel blockers slow rate of AV-conduction in patients with atrial

fibrillation

Includes Verapamil – blocks Na+ channels in addition to Ca2+;

also slows SA node in tachycardia Diltiazem

Bradyarrhythmias

Resting heart rate of <60/min

Classified as Atrial/AV Nodal/Ventricular

Management:

• Acute→ iv atropine

• Permanent→ Pacemakers.

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EXPERIMENTAL EVALUATION OF ANTIARRHYTHMIC DRUG ACTION…………..

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Evaluation of Antiarrhythmic Drug Action

In-Vitro Models:

1) Isolated guinea pig papillary muscle.2) Langendorff technique3) Acetylcholine & potassium Induced arrhythmia

In-Vivo Methods:

Chemically induced arrhythmiaElectrically induced arrhythmiaMechanically induced arrhythmia Exercise Induced Arrhythmia

EVALUATION OF ANTIARRHYTHMIC DRUGS

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IN VIVO METHODS

IN-VIVO METHODS : 

I. Chemically induced arrhythmia

II. Electrically induced arrhythmia

III. Mechanically induced arrhythmia

IV. Exercise Induced arrhythmia.

I.CHEMICALLY INDUCED ARRHTHMIA

A large number of chemical agents alone or in combination are capable of inducing arrhythmia.

ACONITINE ANTAGONISM IN RATSPRINCIPLE: Aconite persistently activate

sodium channel.METHOD:

Continues infusion in saphenous vein

ACONITE 5mg/kg dissolved in 0.1 N HN03

MONITOR LEAD IIECG EVERY 30

SECONDS

Anaesthetize with Urathene

1.25 g/kg

Test compound 3 mg/kg orally

or IV 5 minutes before aconite infusion

EVALUATION

The anti-arrhythmic effect of the test compound is measured by the amount of aconitine/100 gm animal (infusion duration ), required to precipitate...

Ventricular extra systoles. Ventricular tachycardia. Ventricular fibrillation and death. E.g- procainamide 5 mg/kg IV & lidocaine 5 mg/kg IV leads

to increase in lethal dose by 65%.

DIGOXIN INDUCED ARRHYTHMIA IN GUINEA PIGS

PRINICPLE:Over dose of cardiac glycosides induces ventricular extrasystoles, ventricular fibrillation, and finally death.

METHOD :Anesthetised male guinea pigs.(Marioth 350-500 gms)

Trachea, jugular vein and carotid artery are catheterized.

Test grp receives Test drug either orally 1 hr or iv 1 min prior to the infusion while controlol group receieves digoxin infusion only at rate of 85 mg / kg in 0.266 ml/min. until cardiac arrest occurs.

Lead III ECG RECORDED

EVALUATION

The period until the onset of ventricular extra systoles, ventricular fibrillation and cardiac arrest is recorded.

Total amount of infused Digoxin to induce ventricular extra systoles, or ventricular fibrillation and cardiac arrest is calculated.

Using Student’s t-test the doses of digoxin needed to induce VES, VF and Cardiac arrest respectivelyafter treatment with aniarrhythmic drugs are compared with control receiving digoxin only.

Eg- Standard drugs are lidocaine 3 mg/kg iv .

STROPHANTHIN OR OUABAIN INDUCED ARRHYTHMIA IN DOG: 

Principle :Strophanthin K induces ventricular tachycardia and multifocal ventricular arrhythmia in dogs.

METHOD:   Dogs of either sex are first anesthetized & artificial respiration

is given

Two peripheral veins are cannulated for the administration of the arrhythmia

inducing substance and the test compound.

For intraduodenal administration of the test drug, the duodenum is cannulated..

METHOD CTD..

Strophanthin K administered by continuous i.v infusion at a rate of 3mg/kg/min

When the arrhythmias are stable for 10 min, the test substance is

administered i.v ( 1.0 and 5.0 mg/kg) or i.d ( 10 and 30 mg/kg)

ECG recordings are obtained at 0.5, 1, 2, 5 and 10 min following administration of test drugs and further duration increased if required

EVALUATION

Ajmalin , quinidine and lidocaine reestablish normal sinus rhythm at 1 mg/kg ,3 mg/kg iv and 10 mg/kg id.

Test compound is said to have an ant

arrhythmic effect if extra systoles

disappear within 15 min .

The test drug is considered to have “

NO Effect” if it does not improve strophanthin intoxication within 60

min.

 Test compound is said to have an ant arrhythmic effect if the extra systoles immediately disappear . If not then the increasing doses are administered at 15 min- intervals. If the test substance does reverse the arrhythmias the next dose is administered after the reappearance of stable arrhythmias.

I.DI.V

ADRENALINE INDUCED ARRHTHMIA

PRINCIPLE: Adrenaline at high dose may precipitate arrhythmia.

METHOD:

Evaluation: A test compound is said to have antiarrhythmic effect if the extrasystole disappears immediately after drug administration.

Dogs (10-11 kg) are anaesthetized with pentobarbitone (30-

40 mg/kg ) i.p

Femoral vein is cannulated and

adrenaline is infused at a rate of 2-2.5 mg/kg via femoral cannula

Test drug is administered 3 mins. After adrenaline infusion and

Lead II ECG Recorded.

HALOTHANE-ADRENALINE ARRHYTHMIA Normal pacemaker activity of the heart is under the control

of sympathetic and vagal influences

Sympathomimetic drugs are known to increase pacemaker activity

Certain anesthetics, are known to highly sensitize the myocardium to catecholamines

Dogs and Guinea pigs

METHOD

1% halothane vaporized by 100% oxygen used for anesthesia

The infusion rate around 2 – 3 µg/kg/min

Intravenous infusion of adrenaline

Adjusting the infusion speed enough to produce stable vt lasting about 20 min

Drugs injected by iv bolus

II.ELECTRICALLY INDUCED ARHYTHMIAS

VENTRICULAR FIBRILLATION ELECTRICAL THRESHOLD

Principle :Ventricular fibrillations can be induced by various tec. Of electrical stimulation like single pulse stimulation , train of pulse stimulation , continous 50 HZ stimulation.

Ventricular fibrillation threshold :The minimal current intensity of the pulse train required to induce sustained ventricular fibrillation.

Requirement:  Animals – Adult dogs (8-12kg) Anesthetic – Sodium pentobarbital (35mg/kg)

PROCEDURE

↓

Sinus node is crushed and electrical stimulation is provided with Ag-AgCl stimulating electrode embedded in a

Teflon disc sutured to anterior surface of left venticle.

Chest cavity is openedHeart suspended in pericardial

cradle

Artificial respiration – Harvard respiratory pumpB.P – monitored

Body temperature – maintained by thermal blanket

Adult dogs are anaesthetized and heart is exposed.

PROCEDURE CTD…

Test drug/ std/control Drugs are administered through

the femoral vein.

Anodal const. current for 400ms is applied through the

driving electrode

ECG of lead II is recorded

EVALUATION

To determine VFT :- A 0.2 to 1.8 second train of 50 Hz pulses is delivered 100 ms after every 18thbasic driving stimulus. The current intensity is increased from diastolic threshold. When ventricular fibrillation occurs, the heart is immedietely defibrilleted and allowed to recover for 15-20 mins. 

VFT is determined before and after administration of test drugs at given time intervals.

Compared using student - t Test.

PROGRAMMED ELECTRICAL STIMULATION INDUCED RE- ENTRY ARRHYTHMIA

In dogs with old MI reopening of thoracic incision

Bipolar electrodes sutured on the non- infarcted left ventricle

3 premature extra stimuli applied to induce vt or vf If sustained vt or vf occurred, epicardial defibrillation

performed to stop them

After 2 control runs, iv bolus injection of drug given

Same protocol of arrhythmia induction repeated

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COMMENTS

Since arrhythmias induced by applying premature extra stimuli

mechanism of generation is thought to be re-entry around the scar tissue of the old MI.

Drug effects demonstrated by the change in severity before and after the drug administration

This arrhythmia model can used to demonstrate the proarrhythmic potentials

III.MECHANICALLY INDUCED ARRHYTHMIA Coronary artery

occlusion/reperfusion arrhythmia

CORONARY ARTERY OCCLUSION/REPERFUSION ARRHYTHMIA

Arrhythmias –induced directly by ischemia and reperfusion

• Coronary artery ligation in anesthetized dog results in:

↑ in HR ↑in heart contractility ↑ in BP Ventricular arrhythmias

REQUIREMENTS

Animals – Dogs (20-25Kg)Anesthetic – Thiobutobarbital sodium (30mg/kg)

PROCEDURE:Animals – selected

↓Anesthetized

↓Artificial respiration – positive pressure respirator

↓Femoral artery – cannulated and connected to

pressure transducer↓

Chest cavity –openedLAD is exposed

↓

Silk suture is placed around LAD↓

After 45 min(equilibration) – test/std/control- administered through saphenous vein

↓After 20 min- ligature of coronary artery is

closed for 90 min↓

Occlusion released – reperfusion period maintained for 30 min.

• All the parameters – recorded• At the end – surviving animals are sacrificed

by an overdose of Pentobarbital sodium.

EVALUATION

Mortality Hemodynamics Arrhythmia Ventricular fibrillation % animals with VF.

CANINE TWO-STAGE CORONARY LIGATION ARRHYTHMIA

“Two-stage” first stage is the stage of partial occlusion

second stage of permanent

occlusion

METHOD

In the first stage, isolated LAD surgically isolated

The first ligature was drawn snugly but not tightly around the artery

a state of partial occlusion for 30 min then chest is closed

electrocardiogram (ECG) shows only premature ventricular contractions (PVC)

then another suture is used to completely occlude the LAD

Arrhythmia develops 24-48 hrs after ligation and abate in 3-5 days

CONTD….

Arrhythmic ratio:

The number of ventricular ectopic beats (/min)

Total QRS complexes (/min).

For example, the arrhythmic ratio is 0 during the sinus rhythm, while it is 1 during ventricular tachycardia.

ADVANTAGES Produces lesser mortality as compared to complete

occlusion

Very stable arrhythmias, PVC and VT can be obtained which usually appear several hours later

Thus resembles late arrhythmias in post mi patients

Another advantage :- Drugs administered in a conscious state evaluation cns side effects

LIMITATIONS

Cardiac surgery under anesthesia in a sterile environment is needed

The technique of LAD isolation requires skill

Guinea pigs never develop ischemia by in vivo coronary ligation

IV .EXERCISE INDUCED ARRHYTHMIA

EXERCISE INDUCED VENTRICULAR FIBRILLATION PURPOSE AND RATIONALE: Tests combining coronary constriction with physical

exercise may resemble most closely the situation in coronary patients

• REQUIREMENTS:

Animals – Mongrel dogs (15 -19 kg)

Anesthetic – Sodium pentobarbitone (10mg/kg) i.v.

SURGICAL PREPARATION:

Animals – selected

↓

Anesthetized

↓

Chest cavity – opened

↓

Heart suspended in pericardial cradle

↓

Around left circumflex artery – Doppler flow inducer- to measure blood pressure

- Hydraulic occluder - to occlude coronary artery are placed

↓Pair of insulated silver coated wires – sutured on left and

right ventricles- measure HR (By Gould biotachometer)

↓

Occlusion of LAD(Two stage)

↓

Myocardial infarction

↓

After 24 hrs- test drug/std/control - administered

During this experiment:• Transdermal fentanyl patch (↓post operative discomfort)• Bupivacaine HCl• Antibiotic therapy(amoxicillin)

EXERCISE-PLUS-ISCHEMIA TEST

3-4 weeks after the production of MI

↓

Animals – run on a motor –driven treadmill at speed

6.4 km/hr (o%) grade.

↓

Work load - ↑every 3 min for total of 18 mins(0,4,8,12,16%)

↓

During last minute-treadmill is stopped- left circum flex artery- occluded for additional 1 min.

↓

After 10-20 sec of VF – defibrillation is achieved without any delay by placing large metal plates across animal’s chest.

EVALUATION: The exercise plus ischemia test is repeated after administration of the test drug and compared to control (saline) group.The effect of drugs intervention on arrhythmia formation are determined using chi square test with yates correction.

IN VITRO METHOD:

  1) Isolated guinea pig papillary muscle. 2) Langendorff technique 3) Acetylcholine & potassium Induced

arrhythmia

1)ANTI-ARRHYTHMIC ACTIVITY IN THE ISOLATED RIGHT VENTRICULAR GUINEA-PIG PAPILLARY MUSCLE: 

Principle: In right ventricular guinea pig papillary muscle developed tension (DT), excitability (EX), and effective refractory period (ERP) are measured.

METHOD:The heart is removed & placed into a pre-

warmed, pre-oxygenated PSS & right ventricle is opened

The tendinous end of the papillary muscle is ligated with a silk thread and the chordae

tendinae are freed from the ventricle

The preparation is mounted in organ bath & experimental conditions are maintained

The silk thread is used to connect the muscle to forced transducer and muscles are field stimulated to contract isometrically at a

duration of 1 ms.

Pulses are delivered using constant voltage stimulator and

the developed tension is recorded using polygraph recorder.

The force frequency curve is obtained by measuring the

developed tension over a range of stimulus frequencies

(0.3,0.5,0.8,1.0,1.2 HZ)

The percentage change in post treatment versus pretreatment

developed tension at 1 HZ is used to quantitate the agents inotropic effect.

EVALUATION:

Change in Effective Refractory Period (Post treatment minus pretreatment)

Degree of shift in the strength-duration curve.i.e.(area between post and pre treatment curve)

percentage changes in post treatment developed tension. Duration of action potential. Contraction force. The results of above calculations are to classify the

compounds as class I ,III or IV antiarrhythmic agents on the basis of its effect on developed tension, excitability and effective refractory period.

EVALUATION MOA OF DRUG

EXCITABILITY Na+ Channel

Contraction Force Ca+2 Channel

Effective Refractory period

K + Channel

LANGENDORFF TECHNIQUE

PRINCIPLE: Heart is perfused in a retrograde direction from aorta either at constant pressure or at constant flow with oxygenated saline soln.

Retrograde perfusion closes the aortic valve , just as in situ heart during diastole .

The perfusate is displaced through the coronary artery using a canula inserted in the ascending aorta following of the coronary sinus and opened right atrium and flows out via the right ventricle and pulmonary artery.

PROCEDURE

Animal – Guinea pig (300-500g)

Animal – selected

Sacrificed (stunning)

heart – removed – placed in Ringer’s solution

(37 C)⁰

Aorta – located and cut – cannulated with Ringer’s solution (perfused at 40 mm Hg)

Ligature – placed around LAD

Ligature – placed around LAD

Test /std/control - administered.

Occluded for 10 minutes

reperfusion

ECG electrode – pulsatile stimulation, induction of

arrhythmia

Heart rate and contractile force measured

Heart rate measured through

chronometer coupled to polygraph, Contractile force measured by force

transducer. Incidence and duration of ventricular

fibrillation or ventricular tachycardia is recorded in the control as well as test group.

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3)ACETYLCHOLINE & POTASSIUM INDUCED ARRHYTHMIA New Zealand White rabbits 0.5 to 3 kg . The animals are sacrified and heart removed

immediately.Atria dissected from other tissue in Ringer’s solution.

Fibrillation is produced when atria are exposed to Acetylcholine 3x10-4 g/ml or 0.1 gm potassium chloride.

After 5 mins exposure to Ach. Or KCL the atria are stimulated with rectangular pulses of 0.75 ms duration of 10 V.

A mechanical record is taken on kymograph. Controlled arrhythmia are produced and allowed

to continue for 6 to 10 mins. After rest period of 30 mins test compound is

added to bath. Evaluation:- Test compound is found to be

effective if fibrillation disappears immediately or within 5 mins following test drug supplementation to organ bath.

Genetic models

Mutations in the γ 2 subunit (PRKAG2) of AMP activated protein kinase produce an unusual human cardiomyopathy characterized by ventricular hypertrophy and wolf–parkinson white syndrome .

Mutations of the K+ channel genes HERG and KVLQT 1 cause the autosomal dominant long QT syndrome,

Lande et al., Evaluated a transgenic mouse over-expressing a dominant negative kvlqt 1 isoform, as an in vivo screening model for ikr blocking drugs.

Transgenic mice over-expressing the inflammatory cytokine tumour necrosis factor tnf-α (tnf-α mice) in the heart develop a progressive heart failure syndrome . These transgenic animals are more prone to re-entrant arrhythmia.

HUMAN AND MOUSE CARDIAC GENES RELATED TO INHERITED ARRHYTHMIA

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Arrhythmia type Experimental modelWolff Parkinson white

syndromeTransgenic PRKAG2 model

Atrial Flutter Atrial flutter induced by Ach and rapid pacing.Atrial flutter by aconite.Canine right atrial occlusion injury model.

Atrial Fibrillation Atrial fibrillation in the isolated langendorff perfused heart.Canine model of chronic atrial fibrillation.PACAP-27 induced atrial fibrillation.

Ventricular Fibrillation Ventricular fibrillation electrical threshold.Canine model of two stage ligation.Ventricular arrhythmia during exercise by ischemia.

CLINICAL EVALUATION:

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BIOEQUIVALENCE STUDY

Inclusion criteria: A healthy male or female 18 to 59 years of age. BMI range - 18-35 kg/m2, No significant disease or abnormal laboratory values Normal 12-lead ECG Adequately informed of the nature and risks of the study written informed consent

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EXCLUSION CRITERIA

Women who are pregnant or breast feeding. Known hypersensitivity or allergy to drug. A history or presence of asthma or other pulmonary

disease, thyroid disease (hypo- or hyperthyroidism), hepatitis or other liver disease.

Any Medical Disease or surgical condition. The presence of abnormal lab values which are

considered clinically significant. History of smoking or alcohol within past 1 year.

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STUDY DESIGNS IN IMPLANTABLE CARDIOVERTER-DEFIBRILLATOR TRIALS

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MINIMAL CLINICAL PARAMETERS THAT SHOULD BE STUDIED AT BASELINE

Left ventricular ejection fractionTreatment at enrolmentAntiarrhythmic drugsRhythm control drugsRate control drugsAnticoagulationAntihypertensive therapy (special report of angiotensinReceptor inhibition is suggested)Other cardiac medicationConcomitant cardiac disease

Age, genderType of AF (first detected, paroxysmal, Persistent, permanent)Duration of AF since first detectionPrior antiarrhythmic drug treatmentNumber of antiarrhythmic drugs testedNumber of cardioversionsNumber of catheter ablations or surgical interventionsCHADS2 scorePrior antithrombotic treatmentDuration of anticoagulation (vitamin K antagonists,other anticoagulant)Anti-platelet treatment (aspirin, clopidogrel, etc)Symptoms due to AFArrhythmia-related symptoms (EHRA score)Prior stroke/transitoric ischaemic attack

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PRIMARY OUTCOME PARAMETER

Death: Most Important primary outcome. All-cause death should be classified in the following groups. Non-cardiovascular, excluding sudden death Cardiovascular death Cardiac Sudden (including arrhythmic, myocardial infarction,others) Non-sudden Vascular (e.g. embolic, subarachnoidal bleeds, stroke,

other) Treatment- or procedure-related (is also a serious adverse

event)

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SECONDARY OUTCOME PARAMETERS

Symptoms and quality of life

Recommended as secondary outcome parameter No reliable instruments to quantify them Sevirity of atrial fibrillation (SAF SCALE)

Atrial fibrillation symptoms scale (AFSS)

EHRA atrial fibrillation symptoms classification

T/t expected to primarily affect symptoms and quality of life

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EHRA ATRIAL FIBRILLATION SYMPTOMS CLASSIFICATION

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ASSESSMENT OF RHYTHM & ECG-BASED OUTCOME PARAMETERS

AVAILABLE ECG METHODS•Non-continuous standard ECG recordingSymptom-activated ECG (. During triggered visits,.Patient-activated devices)Algorithm-activated (device monitors rhythm)ScheduledResting ECGTranstelephonic monitoring(24–168 h) Holter recordingLoop recorders•Continuous ECG monitoringPacemakers/implanted defibrillatorsECG garment equipped with radio data transmission(E.C.G. GSM-based)

ECG-based outcome parametersFreedom from AF (suitable for time-based assessment)Change in AF pattern (e.G. Altered AF burden, altered AF type,Among many others)Proarrhythmia (e.G. Sudden death, ventricular tachycardia,Torsades de pointes, atrial flutter, bradycardia, AV nodalBlock)Ventricular rate during AF at rest and during exercise

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CURRENT STATUS OF ANTIARRHYTHMIC DRUGS

Based on results of large Randomized controlled trials

Cardioversion /defibrillator devices as compared to

Antiarrhythmic drugs have proved to

Be superior in prolonging survival

CONCLUSION

Although no animal model can accurately resemble with human disease condition and species differences also exist, close similarities with humans suffering from or threatened by arrhythmias can be developed by selecting appropriate model and species.

Rather than a single model or experimental technique, combinations of investigations, like isolated heart (langendorff arrangement or working heart), whole hearts in anesthetized or conscious animals, excised cardiac preparations, testing the function can be used.

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