JOURNAL CLUB

MARIA PINO

PGY-2 INTERNAL MEDICINE

PHASES OF DEPOLARIZATION IN THE

CARDIAC MUSCLE

• PHASE 4 - NA+ AND CA++ CHANNELS ARE CLOSED. K+

CHANNELS ARE OPEN. RESTING POTENTIAL -90MV

• PHASE 0 - MEMBRANE POTENTIAL LESS ( - ) → NA+

CHANNELS OPEN. NA+ ENTERS THE CELL. MEMBRANE V

APPROACHES THRESHOLD ( - 70MV). CA++ CHANNELS

ALSO OPEN (-40MV). THE CELL DEPOLARIZES TRANSIENTLY

TO A NET (+) POTENTIAL.

• PHASE 1 - BRIEF CURRENT OF DEPOLARIZATION RETURNS THE

MEMBRANE POTENTIAL TO 0. CARRIED BY THE OUTWARD

FLOW OF K+ THROUGH A TRANSIENTLY ACTIVATED K+

CHANNELS (ITO)

• PHASE 2 - PLATEAU PHASE, THE LEVEL OF THE PLATEAU IS SET

BY ITO. CA++ INFLUX IS BALANCED BY AN EQUAL K+ EFFLUX,

THROUGH DELAYED RECTIFIER K+ CHANNELS.

• PHASE 3 - RETURNS THE TRANSMEMBRANE V BACK TO

RESTING POTENTIAL (-90MV). CONTINUED OUTWARD K+

CURRENT AND LOW MEMBRANE PERMEABILITY FOR OTHER

CATIONS.

REFRACTORY PERIODS

The cell is completely

unexcitable

Stimulation produces

a localized AP not

strong enough to

propagate

Stimulation

triggers an AP

that is

conducted,

but its rate of

rise is slower

A weaker-

than-normal

stimulus can

trigger an AP

NORMAL IMPULSE FORMATION

• ELECTRIC IMPULSE FORMATION IN THE HEART ARISES FROM INTRINSIC

AUTOMATICITY OF SPECIALIZED CARDIAC CELLS.

• AUTOMATICITY - CELL’S ABILITY TO DEPOLARIZE ITSELF TO A

THRESHOLD VOLTAGE TO GENERATE A SPONTANEOUS AP

• THE CELLS OF THE SPECIALIZED CONDUCTING SYSTEM (SA NODE,

AV NODE, VENTRICULAR CONDUCTING SYSTEM) POSSES NATURAL

AUTOMATICITY AND ARE TERMED PACEMAKER CELLS

• IN PATHOLOGIC SITUATIONS, MYOCARDIAL CELLS OUTSIDE THE

CONDUCTING SYSTEM MAY ALSO ACQUIRE AUTOMATICITY

ACTION POTENTIAL OF PACEMAKER

CELLS

• CELLS WITH AUTOMATICITY DO NOT

HAVE A STATIC RESTING VOLTAGE

• THEY INHERENTLY DISPLAY GRADUAL

DEPOLARIZATION DURING PHASE 4 OF

THE AP

• PACEMAKER CURRENT (IF) “FUNNY

CURRENT” - THE CHANNELS CARRYING

THIS CURRENT ARE ACTIVATED BY

HYPERPOLARIZATION (INCREASINGLY

NEGATIVE VOLTAGE) AND MAINLY

CONDUCT NA+ IONS

• IF CHANNELS BEGIN TO OPEN WHEN THE

MEMBRANE VOLTAGE BECOMES MORE

NEGATIVE THAN APPROX - 50 MV

Upstroke is

much slower

than that of

Purkinje system

PACEMAKER CELLS

• 3 VARIABLES INFLUENCE HOW FAST

THE MEMBRANE POTENTIAL

REACHES THRESHOLD

1. THE RATE (SLOPE) OF PHASE

4 SPONTANEOUS

DEPOLARIZATION

2. MAXIMUM NEGATIVE

DIASTOLIC POTENTIAL (MDP)

3. THRESHOLD POTENTIAL (TP)

Reduced If makes the

slope of phase 4 less

steep - time to reach

TP increases

Cardiac action potentials

ATRIAL ELECTROPHYSIOLOGY

• DIFFERENCES IN ION CHANNEL EXPRESSION

CONTRIBUTE TO THE VULNERABILITY OF THE

ATRIA TO AF.

• I KUR IS EXPRESSED MOSTLY IN ATRIAL

MYOCYTES. CONTRIBUTES TO PHASE 2.DRUGS BLOCKING I KUR PROLONG THE

ATRIAL ERP AND ↓ STABILITY OF AF.

• ↑ I KACH EXPRESSION, CAUSES VAGAL-ACTIVATED INWARD RECTIFIER CURRENT

DURING PHASE 3 AND 4. VAGAL

STIMULATION SHORTENS THE APD AND

ERP MAKING AF MORE STABLE.

• ↓ I K1 EXPRESSION ( INWARD RECTIFIER

CURRENT) CAUSES HIGHER RMP, MAKING

ATRIAL MYOCYTES MORE EXCITABLE THAN

VENTRICULAR MYOCYTES.

ATRIAL ANATOMY AND VARIATIONS

IN ATRIAL ELECTROPHYSIOLOGY

• RAPID ACTIVATION WITH SHORT

CYCLE LENGTHS CAN OCCUR IN

PULMONARY VEINS (PVS) AN CAN

CAUSE PAROXYSMS OF AF.

SIMILAR ACTIVITY SVC, VEIN OF

MARSHALL (VOM).

• PV HAVE ↓ ICAL AND ITO

COMPARED ATRIAL MYOCYTES

ALONG WITH ↑ IKR AND IKS →

SHORTER APD IN PV MYOCYTES

COMPARED TO THE REST OF THE

ATRIUM.

ATRIAL ANATOMY AND VARIATIONS

IN ATRIAL ELECTROPHYSIOLOGY

• PATIENTS WITH AF HAVE BEEN

FOUND TO HAVE AREAS OF

THICKENED PV WALLS AND MORE

FIBROSIS THAN NO AF PATIENTS

• PECULIAR HISTOLOGY IS

REFLECTED IN THE

ELECTROPHYSIOLOGY. THE PV-LA

JUNCTION DEMONSTRATES

DELAYED AND HETEROGENOUS

CONDUCTION PATTERNS, SETTING

UP SUBSTRATE FOR CONDUCTION

BLOCK - REENTRY → AF IN

RESPONSE TO RAPID PACING AND

EXTRASTIMULUS TESTING.

ATRIAL REMODELING IN AF

• AF IS A PROGRESSIVE ARRHYTHMIA

• 14 TO 24 % PTS WITH PAROXYSMAL AF WILL DEVELOP PERSISTENT AF

• CONVERSION OF AF TO NSR BECOMES MORE DIFFICULT WHEN AF HAS

BEEN PRESENT FOR A LONG TIME

• REMODELING PROCESS : CASCADE OF ELECTRICAL AND STRUCTURAL

CHANGES N THE ATRIA THAT LEAD TO PERPETUATION – “AF BEGETS AF”

COMPONENTS OF ATRIAL REMODELING

• ELECTRICAL REMODELING – ALTERATIONS IN SEVERAL ION

CHANNELS WITH SUBSEQUENT SHORTENING OF THE AP AND

MEMBRANE HYPERPOLARIZATION

THREE MAJOR CHANGES UNDERLIE THE AP TRIANGULARIZATION:

• DOWNREGULATION OF INWARD CURRENT ICAL

• UPREGULATION OF THE INWARD RECTIFIER CURRENT

IK1

• ACTIVATION OF IKACH

REVERSIBLE AFTER SNR RESTORATION

CALCIUM OVERLOAD ALTERED CALCIUM HANDLING

• CONTRACTILE REMODELING – LOSS OF ATRIALCONTRACTILITY ATRIAL DILATION (↑ ?INCREASE ATRIAL

THROMBOSIS)

- STRUCTURAL REMODELING - CHRONIC ATRIAL STRETCH AND

DEFORMATION ARE MAJOR ACTIVATORS OF THE SIGNALING

PATHWAYS LEADING TO CELLULAR HYPERTROPHY AND

DIFFUSE/PATCHY INTERSTITIAL FIBROSIS

• RESULTS IN LOCAL CONDUCTION HETEROGENEITIES – AF

ELF PERPETUATION.

• MAIN MECHANISM RESPONSIBLE FOR AF PROGRESSION

Principal factors involved in inducing and maintaining AF

WL = RP x CV

Prolong

refractory

period

Impair

conduction

even more

Controlling AF

ReentryAutomaticityAbnormal automaticity

Myocardial cells have few or no

activated PM channels, do they gain If

?.

Membranes become “leaky” RP

becomes less negative.Triggered activity

↑ Ca++

Catecholamine

stimulation

or Digitalis

intoxication

ATRIAL FIBRILLATION MEDICATIONS

NA+ CHANNEL BLOCKERS (CLASS I ANTIARRHYTHMICS)

BIND TO AND BLOCK THE FAST NA+ CHANNELS THAT

ARE RESPONSIBLE FOR THE RAPID DEPOLARIZATION

(PHASE 0) ↓ SLOPE OF PHASE 0, AND AMPLITUDE OF

THE ACTION POTENTIAL.

SOME INCREASE THE ERP (CLASS IA). DUE TO DRUG ACTIONS ON K+ CHANNELS INVOLVED

IN PHASE 3 REPOLARIZATION OF ACTION POTENTIALS.

SODIUM-CHANNEL BLOCKADE:IC > IA > IB

INCREASING THE ERP:IA > IC > IB (↓)

EFFECTS ON AUTOMATICITY

CLASS I ANTIARRHYTHMICS CAN SUPPRESS

ABNORMAL AUTOMATICITY BY DECREASING THE SLOPE

OF PHASE 4, GENERATED BY PACEMAKER CURRENTS

(INHIBITION OF PACEMAKER CHANNELS)

INDIRECT VAGAL EFFECTS - ANTICHOLINERGIC

ACTIONS. INCREASING SA RATE AND AV CONDUCTION, WHICH CAN OFFSET THE DIRECT

EFFECTS OF THE DRUGS ON THESE TISSUES.

K+ CHANNEL BLOCKERS (CLASS III

ANTIARRHYTHMICS)

BLOCK THE K+ CHANNELS RESPONSIBLE

FOR PHASE 3 REPOLARIZATION.

SLOWS (DELAYS) REPOLARIZATION →

INCREASES APD AND EFFECTIVE

REFRACTORY PERIOD (ERP).

LITTLE EFFECT ON PHASE 0

DEPOLARIZATION OR CONDUCTION

VELOCITY.

Β - BLOCKERS (CLASS II ANTIARRHYTHMICS)

SYMPATHETIC STIMULATION (Β1 - ADRENERGIC

RECEPTORS) - ↑ SA NODE AUTOMATICITY

• ↑ THE OPEN PROBABILITY OF THE PACEMAKER

CHANNELS, INCREASING IF AND LEADING TO A

STEEPER PHASE 4. SA NODE REACHES THRESHOLD

AND FIRES EARLIER - HR INCREASES

• ↑ THE PROBABILITY THAT VOLTAGE-SENSITIVE CA++

CHANNELS ARE CAPABLE OF OPENING (PHASE 0 IN

PM CELLS) THEREFORE DIASTOLIC

DEPOLARIZATION REACHES THRESHOLD POTENTIAL

EARLIER (TP BECOMES MORE NEGATIVE)

CCBS (CLASS IV ANTIARRHYTHMICS)

SELECTIVELY BLOCK OF L-TYPE CA++ CHANNELS

MOST POTENT IN TISSUES IN WHICH THE AP DEPENDS

ON CA++ CURRENTS (SA AND AV NODES)

↓ RATE OF RISE OF PHASE 0 DEPOLARIZATION AND

CONDUCTION VELOCITY

LENGTHENS THE RP OF THE AV NODE

THESE AGENTS ALSO RAISE THE TP AT THE SA NODE.

THE RESULTING

ANTIARRHYTHMIC DRUGS

Condition Drug Comments

Sinus tachycardia Class II, IVOther underlying causes

may need treatment

Atrial fibrillation/flutterClass IA, IC, II, III, IV

digitalis

Ventricular rate control is

important goal;

anticoagulation is required

Paroxysmal supraventricular

tachycardia

Class IA, IC, II, III, IV

adenosine

AV block atropine Acute reversal

Ventricular tachycardia Class I, II, III

Premature ventricular

complexes

Class II, IV

magnesium sulfate

PVCs are often benign and

do not require treatment

Digitalis toxicityClass IB

magnesium sulfate

ANTIARRHYTHMIC DRUGS

ClassBasic

MechanismComments Examples

INa+ channel

blockadeReduce phase 0 slope and peak of action potential.

IA - moderateModerate reduction in phase 0 slope; increase APD;

increase ERP.

Quinidine

Procainamide

Disopyramide

IB - weakSmall reduction in phase 0 slope; reduce APD; decrease

ERP.

Lidocaine

Mexiletine

IC - strongPronounced reduction in phase 0 slope; no effect on APD

or ERP.

Flecainide

Propafenone

II β -blockade Block sympathetic activity; reduce rate and conduction.

Propranolol

Esmolol

Metoprolol

IIIK+ channel

blockade

Delay repolarization (phase 3) and thereby increase action

potential duration and effective refractory period.

Amiodarone

Dronedarone

Sotalol

Ibutilide*

Dofetilide

IVCa++ channel

blockade

Block L-type calcium-channels; most effective at SA and AV

nodes; reduce rate and conduction.

Verapamil

Diltiazem

AHA/ ACC/ HRS AF GUIDELINE ON “RHYTHM-CONTROL

STRATEGY”

RCTS COMPARING OUTCOMES OF A RHYTHM-CONTROL STRATEGY USING ANTIARRHYTHMIC DRUGS WITH A

RATE-CONTROL STRATEGY IN PATIENTS WITH AF FAILED TO SHOW A SUPERIORITY OF RHYTHM CONTROL FOR

EITHER STRATEGY ON MORTALITY.

SEVERAL CONSIDERATIONS FAVOR PURSUING A RHYTHM-CONTROL STRATEGY:

• PERSISTENT SYMPTOMS ASSOCIATED WITH AF (MOST COMPELLING INDICATION)

• DIFFICULTY IN ACHIEVING ADEQUATE RATE CONTROL

• YOUNGER PATIENT AGE

• TACHYCARDIA-MEDIATED CARDIOMYOPATHY

• FIRST EPISODE OF AF

• AF THAT IS PRECIPITATED BY AN ACUTE ILLNESS

• PATIENT PREFERENCE

AFFIRM TRIAL: DESIGN

• MULTICENTER, PARALLEL-GROUP, RANDOMIZED, CONTROLLED TRIAL

• ITT ANALYSIS: PTS WERE ANALYZED ACCORDING TO THEIR

ASSIGNED TREATMENT

• N=4,060 PATIENTS WITH NONVALVULAR ATRIAL FIBRILLATION

• RATE-CONTROL STRATEGY (N=2,027) • RHYTHM-CONTROL STRATEGY (N=2,033)

• SETTING: 213 CLINICAL SITES AND THEIR SATELLITE SITES, INCLUDING UNIVERSITY OF WASHINGTON

• MEDIAN FOLLOW-UP: 3.5 YEARS

• PRIMARY OUTCOME: ALL-CAUSE MORTALITY AT 5 YEARS

POPULATION

INCLUSION CRITERIA

• AGE ≥65 YEARS

• AGE <65 YEARS IF ANOTHER RISK FACTOR FOR STROKE OR DEATH(HTN, DM, CHF, PRIOR STROKE/TIA, SYSTEMIC EMBOLISM, LA> 50 MM, LVEF <40%, LV FRACTIONAL SHORTENING <25%)

• AF LIKELY TO BE RECURRENT (“IN THE CLINICAL JUDGMENT OF THE

INVESTIGATORS”)• AF LIKELY TO CAUSE ILLNESS OR DEATH FOR THE PARTICIPANT (“IN THE

CLINICAL JUDGMENT OF THE INVESTIGATORS”)• LONG-TERM TREATMENT OF AF WAS WARRANTED

EXCLUSION CRITERIA• CONTRAINDICATION TO ANTICOAGULATION THERAPY

• INELIGIBLE TO UNDERGO TRIALS OF ≥2 MEDICATIONS IN EITHER TREATMENT

STRATEGY

INTERVENTIONS

RATE-CONTROL STRATEGY

• THERAPEUTIC TARGET FOR HEART RATE AT REST (<80 BPM) AND DURING ACTIVITY (<110 BPM), WHICH USUALLY CONSISTED OF SIX-MINUTE WALK TEST.

• DRUGS ACCEPTABLE FOR USE INCLUDED:

• CLASS II AGENTS: BETA-BLOCKERS

• CLASS IV AGENTS: CALCIUM-CHANNEL BLOCKERS (VERAPAMIL AND DILTIAZEM)

• CLASS V AGENTS: DIGOXIN

• ANTICOAGULATION WITH WARFARIN (GOAL INR 2-3)

RHYTHM-CONTROL STRATEGY

• ANTI-ARRHYTHMIC AGENT CHOSEN BY TREATING PHYSICIAN. ATTEMPTS TO MAINTAIN SINUS RHYTHM COULD INCLUDE CARDIOVERSION

AS NECESSARY.

• DRUGS ACCEPTABLE FOR USE INCLUDED:

• CLASS IA AGENTS: QUINIDINE, PROCAINAMIDE, DISOPYRAMIDE

• CLASS IC AGENTS: FLECAINIDE, PROPAFENONE, MORICIZINE

• CLASS III AGENTS: AMIODARONE, SOTALOL, DOFETILIDE

• ANTICOAGULATION WITH WARFARIN ENCOURAGED BUT COULD BE STOPPED AT PHYSICIAN'S DISCRETION IF SINUS RHYTHM MAINTAINED

FOR AT LEAST 4, AND PREFERABLY 12, CONSECUTIVE WEEKS.

AFTER THE FAILURE OF AT LEAST TWO TRIALS OF EITHER A RHYTHM-CONTROL DRUG OR A RATE-CONTROL DRUG, PATIENTS COULD BE

CONSIDERED FOR NON-PHARMACOLOGIC THERAPY SUCH AS RADIO-FREQUENCY ABLATION, MAZE PROCEDURE, AND PACING

TECHNIQUES.

• USE OF WARFARIN (RATE VS. RHYTHM-CONTROLLED)

>85% VS. ~70% (P<0.001)

• SINUS RHYTHM AT 5 YEARS (RATE VS. RHYTHM-CONTROLLED)

34.6% (>80% RATE-CONTROLLED) VS. 62.6% (P<0.001)

• CROSS-OVER RATE (RATE- TO RHYTHM-CONTROL VS. RHYTHM- TO RATE-CONTROL)

14.9% VS. 37.5% (P<0.001)

• RADIOFREQUENCY ABLATION USED IN 105 (5.2 PERCENT) OF THE PATIENTS IN THE RATE-

CONTROL GROUP AFTER DRUG FAILURE.

• ELECTRICAL CARDIOVERSION (RHYTHM-CONTROLLED GROUP)

ONCE IN 368 PTS, TWICE IN 214 PTS, AND THREE OR MORE TIMES IN 187 PTS.

RFA IN 14 PTS. IMPLANTABLE ATRIAL CARDIOVERTER IN 3. MAZE PROCEDURE IN 4.

RESULTS

CONCLUSION

• MANAGEMENT OF ATRIAL FIBRILLATION WITH THE RHYTHM-CONTROL

STRATEGY OFFERS NO SURVIVAL ADVANTAGE OVER THE RATE-CONTROL

STRATEGY, AND THERE ARE POTENTIAL ADVANTAGES, SUCH AS A LOWER

RISK OF ADVERSE DRUG EFFECTS, WITH THE RATE-CONTROL STRATEGY.

• ANTICOAGULATION SHOULD BE CONTINUED IN THIS GROUP OF HIGH-

RISK PATIENTS.

POST-AFFIRM WORLD

1. CORLEY S, AFFIRM INVESTIGATORS. 2004 ->SINUS RHYTHM

DECREASED RISK OF DEATH (HR 0.53), AAD INCREASED THE RISK OF

DEATH (HR 1.42)

2. CURTIS AB, AFFIRM INVESTIGATORS. 2004 ->YOUNGER THAN 65 YAND H/O HF - TREND (NO STATISTICALLY SIGNIFICANT) TO DO BETTER W/ RHYTHM CONTROL.

• AF-CHF STUDY (ROY D, ET AL. 2008)->NO DIFFERENCE IN MORTALITY

BETWEEN RHYTHM AND RATE CONTROL IN HEART FAILURE (HR 0.97, 95% CI, 0.8-1.17)

3. IONESCU R,ET AL. 2012->26,130 PTS. 8-YEAR FOLLOW UP. “WITH

INCREASING FOLLOW UP TIME, MORTALITY AMONG PTS WHO NEWLY

INITIATED RHYTHM CONTROL THERAPY GRADUALLY DECREASED RELATIVE

TO RATE CONTROL, REACHING 23% REDUCTION AFTER 8 YEARS OF

FOLLOW UP”.

Ionescu-Ittu R, et al. Arch Intern Med. 2012; 172 (13): 997-1004

Ionescu-Ittu R, et al. Arch Intern Med. 2012; 172 (13): 997-1004

CONCLUSIONS AS OF 2014

• SR IS SAFER THAN ATRIAL FIBRILLATION

• PRESENT RATE CONTROL AND RHYTHM CONTROL DRUGS OFFER NO

SURVIVAL DIFFERENCES BETWEEN EACH OTHER.

• OPTIMAL SCENARIO WOULD BE MORE EFFICIENT RHYTHM CONTROL

WITH LESS SIDE EFFECTS (RFA?, VERNAKALANT?)

T-Test vs. Chi-Squared Test

“The base-line characteristics of patients were compared with chi-square tests and t-tests.”

P-Value

“The probability that results as extreme as or more extreme than those observed would occur if the null

hypothesis were true and the experiment were repeated over and over.”

T-Test

Used to examine the difference between the means of two groups of values, the null hypothesis of which is that the

means are identical.

Chi-Squared

Used to compare the distribution of categorical outcomes in two or more groups, the null hypothesis of which is that the

underlying distributions are identical.

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