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EVALUATION OF ANTIARRHYTHMIC DRUGS
Dr. Nitin Shinde1st Year ResidentLTMMC & GH, Mumbai - 22DATE- 22-02-2014.
2
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.
91
92
STUDY DESIGNS IN IMPLANTABLE CARDIOVERTER-DEFIBRILLATOR TRIALS
93
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
96
97
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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REFERENCES Vogel WH, Schölkens BA. Drug Discovery and Evaluation [Internet]. Vogel HG,
Vogel WH, Schölkens BA, Sandow J, Müller G, Vogel WF, editors. Berlin, Heidelberg: Springer Berlin Heidelberg; 2002. P.208-29.
Pratt C, Camm A. Evaluation of antiarrhythmic drug efficacy in patients with an ICD. Unlimited potential or replete with complexity and problems? Eur. Heart J. [Internet]. 1999 [cited 2014 Feb 21];1538–52.
Mor M, Shalev A, Dror S, Pikovsky O, Beharier O, Moran A, et al. INO-8875, a highly selective A1 adenosine receptor agonist: evaluation of chronotropic, dromotropic, and hemodynamic effects in rats. J. Pharmacol. Exp. Ther. [Internet]. 2013 Jan;344(1):59–67.
Nilles KM, London B. Knockin animal models of inherited arrhythmogenic diseases: what have we learned from them? J. Cardiovasc. Electrophysiol. [Internet]. 2007 Sep [cited 2014 Feb 21];18(10):1117–25.
Bodhankar S, Bhatt L, Nandakumar K. Experimental animal models to induce cardiac arrhythmias. Indian J. Pharmacol. [Internet]. 2005;37(6):348.
Kirchhof P, Auricchio A, Bax J, Crijns H, Camm J, Diener H-C, et al. Outcome
parameters for trials in atrial fibrillation: executive summary. Eur. Heart J. [Internet]. 2007 Nov ;28(22):2803–17.