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842 Cards in this Set

  • Front
  • Back

path electrical activity takes through the heart

starts at the SA node near the SVC

travels to AV node

moves down the his bundle

to the left and right bundle branches

atria and ventricles are electrically isolated from each other by the

annulus fibrosus

gap junctions

pores that join cytoplasm or neighboring cells
ionsfreely move which allows for electrical propogation

electromechanical coupling

electrical activity is the trigger for mechanical activity

it precedes the mechanical activity

electrical signal disruption can lead to mechanical functional problems

Cardiac muscle action potential phases

0 - upstroke

1 - early repolarization

2 - plateau

3 - late repolarization

4 - back to rest

AP specifics in the nodes

slow upstroke

lack a plateau phase

lack a stable resting membrane potential

as soon as they depolarize, they begin to repolarize

AP specifics in the atria, his bundle, purkinje system, ventricles
stable resting potential

more rapid upstroke

early repolarization

plateau phase is prominent
more prominent plateau phases in atria, ventricles, etc are for...

ca induced ca release to happen

longer AP in purkinje and his bundle...

protect that tissue from the activity initiated in the ventricle propagating backwards

fastest conduction velocity in cardiac tissue
purkinje system
order of conduction speed, fastest to slowest, in cardiac tissue
purkinje system

atrial pathways and bundle of his

ventricular muscle

SA node and AV node
faster conducting tissues are
better aligned, well coupled
distribution of ions

More Na outside
More K inside
More Cl outside
More Ca outside

ionic basis of resting membrane potential

Ik1 current

inward rectifier K channel (K is leaking out of the cell down its electrostatic and chemical gradients)

this channel closes when current moves into the cell

resting heartcells behave like _____________ membranes
K-selective
experimentally, the RMP in resting heart cells is

-85mV

cardiac action potentials

fast response

atrial

purkinje

ventricular

cardiac action potentials

slow response
SA and AV nodes
Fast response action potential

Phase 0
Upstroke
At rest Ik1 is open and Na channel is closed

a depolarizing current triggers activation gate of Na channels

they activate and as cell beginsto depolarize the Ik1 channel closes almost immediately (Magnesium blocks it up)

Currents:
I(Na) - Sodium in
Fast response action potential

phase 1
early repolarization

Transient outwork K current
voltage gated K channels

Current
I(to) - k moves out of cell at depolarized potentials

fast response action potential

phase 2
plateau
I(to) current begins to inactivate and close

activation of delayed rectifier K current
L type Ca channels activate allowing calcium in for CICR for muscle contraction

balance of K out and Ca in keeps membrane potential around 0mV

currents:
I(k) - K out
I(Ca) - Ca in

(eventually L type Ca channels will inactivate themselves)
Fast response action potential

phase 3
final repolarization

L type Ca channels inactivate themselves

the delayed rectifier current begins to dominate

the membrane potential moves back to RMP

In late part of phase 3 the magnesium blocking effect on Ik1 is relieved and Ik1 reopens

Ik will eventually close

currents
I(k1) - K out
I(k) - K out

Fast response action potential

Phase 4
rest

After Ik closes it's just Ik1 and the 3Na(out)/2K(in) ATPase

currents
I(k1) - K out

Na/K ATPase

I(KATP/ACh)
ligand gated current
ATP sensitive in cardiac myocytes
opens when ATP drops

during ischemia, AP duration would shorten
less contraction, save some energy
Voltage gated K channels
4 separate subunits form a channel

voltage sensor is the S4 segment

Pore region is the S5-S6 linker

N terminal is where voltage-dependent inactivation happens
voltage gated Na and Ca channels
similar structure to K channels
BUT
each consists of a single subunit containing four repeats

Na and Ca channels are linked together, as opposed to K which are individual
Ik1 - inward rectifier current

resting membrane potential

outward current during phase 3

not voltage gatged

closes at depolarized membrane potentials

not present in pacemaker cells

Ik - delayed rectifier current

outward current during phase 2 and 3

two components I(Kr) and I(Ks)

expressed in pacemaker cells

ways ion currents are modulated
change in available current (carrier concentration or temp)

number of functional channels (changes in gene expression)

probability of activation
Slow response action potential differences
resting potential is less negative because Ik1 is absent

upstroke is due to inward Ca current from L type Ca channels

slow diastolic depolarization during phase 4, instead of remaining locked at rest
rate of sinus node cell firing depends upon
the balance between inward and outward currents
ionic basis of automaticity

currents that contribute to diastolic depolarization

I(f) - inward depolarizing current, induced by hyperpolarization

I(Ca) - inward calcium current

I(K) - outward, delayed rectifier potassium current (I(Kr) and I(Ks))

factors that influence pacemaker rate

slope of diastolic depolarization

threshold potential

minimum diastolic potential

how it affects pacemaker rate

slope of diastolic depolarization
a smaller slope of depolarization means it takes longer to reach threshold potential

it will take longer to fire
how it affects pacemaker rate

threshold potential
increasing threshold potential will make it take longer to reach

it will take longer to fire
how it affects pacemaker rate

minimum diastolic potential
if you have an even more negative minimum diastolic potential, you'll be further away from threshold potential

itwill take longer to fire
pacemaker rate

parasympathetic stimulation
activation of I(KACh channels) - increases K conductance

lowers min diastolic potential

decreases slope of phase 4
pacemaker rate

sympathetic stimulation
activation of I(f) channels -

increases slope of phase 4

no change in min diastolic potential
refractory period
absolute refractory period - during upstroke and depolarization where you can't get another AP to fire at all

relative refractory period - after repolarization has started, an AP could fire but it won't be as effective
positive charge comes at an electrode
positive signal
positive signal moves away from an electrode
(negative signal moves towards it)
negative signal
positive or negative signal passes by an electrode
isoelectric
how many electrodes and how many leads?
10 electrodes

12 leads
all leads are unipolar except
I
II
III
aVR
right arm
aVF

left leg

aVL
left arm
I
right arm to left arm
II
right arm to left leg
III

left arm to left leg

V1

Right sternal 4th intercostal

V2

left sternal 4th intercostal

V3 and V4

mid clavicular

V5

anterior axillary
V6
mid axillary
path of electricity through heart and waveform
starts at SA node

as it travels through RA, the RA contracts and you get a p wave

gets to the AV node iso-electrically

Down the bundle of his to the bundle branches and around is the QRS (ventricular contraction)

Resetting starts from teh outside (repolarization) at the left lateral base
resets outside in and makes the t wave
qrs through the heart
starts in the intraventricular septum, on the edge of the left ventricle

moves away from aVL through the septum going towards aVF

swings around to the rest of the myocardium inside bundle branches to get to rv and lv apex

still going towards aVF and now it's also going towards aVL

moves up the left bundle branch

moving away from aVF and moving rapidly positive towards aVL
time
1 small box
0.04 sec

40 msec
time 1 big box
.2 sec

200 msec
voltage 1 small box
0.1 mV
volrtage 1 big box
0.5 mV
normal PR interval
120 to 200 msec
normal QRS interval
60 to 100 msec
normal QT interval
less than 440 msec (men) or 460 msec (women)
heart rate method 1
count number of small boxes between qrs complexes

divide 1500 by the number f boxes

most useful for fast heartbeats over 100 bpm
heart rate method 2
count off method

each big box you go down in the sequence

300 - 150 - 100 - 75 - 60 - 50
heart rate method 3

number of QRS in the 3 sec marker and multiply by 20

or

number of QRS in the 6 sec marker and multiply by 10

helpful for irregular heart rates

p wave
depolarization of the top chambers
R wave
depolarization of the ventricles
T wave

repolarization of the ventricles

U wave
shrug
five steps to ecg read
rate
rhythm
axis
intervals
morphology
axis
normal
lead I up

aVF up
left axis deviation
I up

aVF down
right axis deviation
I down

aVF up
extreme axis
I down

aVF down
normal axis is between what degrees
-30 (left) and +90 (right)
left axis deviation is between what degrees
-30 to -90
right axis deviation is between what degrees
+90 to +150
extreme axis is between
+150 and -90
left axis deviation causes
inferior wall myocardial infarction

left anterior fascicular block

left ventricular hypertrophy
right axis deviation causes

right ventricular hypertrophy

acute right heart strain (like a massive pulmonary embolism)

left posterior fascicular block

intervals (again)

HR less than 100 bpm

1:1 P to QRS ratio

PR < 200 ms

QRS < 110 ms

QTc < 460 ms

normal p wave in lead II

normal p wave in lead V1

p wave



RA enlargement in lead II

p wave



RA enlargement in lead V1

p wave



LA enlargement in lead II

p wave



LA enlargement in lead V1

RV hypertrophy in V1

RV hypertrophy in V6

RV hypertrophy characteristics on ecg

R > S in V1



right axis deviation


(lead I down, lead aVF up)

LV hypertrophy in V1

LV hypertrophy in V6

LV hypertrophy characteristics in ecg

Deep S wave in V1



R in V5 or V6 is greater than 35 mm



R in aVL is greater than 11 mm



R in lead I is greater than 15 mm

RBBB

LBBB

the normal dynamic

all regions start at the same baseline



ekg baseline is set during electrical diastole when everything is quiet.



no significant gradients exist between regions

ekg changes with ischemia

ekg changes with ischemia

ST elevation

ekg changes with ischemia

ekg changes with ischemia

ST elevation



decreased R wave



Q wave begins

ekg changes with ischemia

ekg changes with ischemia

T wave inversion



Q wave gets deeper

ekg changes with ischemia

ekg changes with ischemia

ST normalizes



T wave inverted

ekg changes with ischemia

ekg changes with ischemia

ST and T normalize



Q wave persists

ischemia and potassium

dysfunction I(k) and I(ATP) lead to potassium leak



the cells dont have ATP/energy



region gets necrotic and swells

ischemia in diastole

ischemic cells leak potassium during phase 4 causing the baseline to be more positive

ischemia in systole

ischemic cells are less positive because



shorter action potential


slower upstroke


lower amplitude

ST segment elevation in MI

injury on the outside region of the muscle, leaking potassium



gradient between the epicardium and endocardium



K going away from the electrode creates a vector away from it and that becomes the new normal baseline



ST segment is actually normal, it looks elevated compared to the new normal baseline

NON ST segment elevation in MI

injured on the inside region of the muscle



leaked potassium creates a vector TOWARD the recording electrode, which forms a new higher baseline



ST region looks depressed during depolarization

MI Q wave

in aVL



goes down because aVL cant see a signal coming towards it until really late



jumps up late when the healthy section at the base is seen

Q waves are normal due to

left to right activation



normal in I, aVF, V5, and V6

Pathologic Q waves

> 40 ms



2 mm deep



more than 25% of the QRS amplitude



seen in V1, V2, V3

anteroseptal leads

v1


v2

anteroapical leads

v3


v4

anterolateral leads

I


aVL


V5


V6

inferior leads

II


III


aVF

current influx at phase 4 of a cardiac pacemaker cell

I(f) influx

AP in a cardiac pacemaker cell

I(f) current

activated by hyperpolarization



channels open when membrane voltage is more negative than -50mV



Mainly conducts Na ions



inward Na flow driven by conc gradient and the negative charge inside the cell

in the pacemaker cells of the SA node...

slow inward Ca current carried by mostly L type Ca channels



progressive decline of outward K current



additional inward Na current via Na/Ca exchanger act by SR Ca (calcium clock)

what are A B and C

what are A B and C

A is normal nodal (slow) AP



B is reduced I(f) which means it takes longer to get to threshold potential so it fires later



C is more negative maximum diastolic potential that makes it take even longer to get to Threshold Potential

natural pacemaker in the normal heart

SA node


beats at 60-100 bpm



faster than other tissues with automaticity

SA node bpm

60-100

AV node/Bundle of His bpm

50-60

Purkinje System bpm

30-40

when an impulse arrives at a cell that has not yet gotten close to threshold

current from the depolarized cell will bring the adjacent cell's membrane potential to threshold level so that it will fire



this is why the fastest autonomic cell will be the dominant pacemaker

latent (ectopic) pacemakers take over if

SA node slows or fails to fire



if conduction abnormalities block the normal depolarization wave from reaching them

enhanced automaticity of latent pacemakers



ectopic beats

impulse premature, relative to normal rhythm



high catecholamine conc can enhance automaticity of latent pacemakers



if the resulting rate of depolarization exceeds that of the sinus node, an ectopic rhythm can develop

ectopic beat commonly induced by

hypoxia



ischemia



electrolyte disturbances



certain drug toxicities (dig)

Abnormal automaticity

cardiac tissue injury can lead to pathologic changes in impulse formation



myocardial cells outside the specialized conduction system can acquire automaticity and spontaneously depolarize



since they arent designed to be pacemakers, they dont carry I(f), but their membranes become leaky



can't maintain conc gradients of ions and the resulting potential becomes less negative



if it becomes less negative than -60mV, gradual phase 4 depolarization is observed, even in non pacemaker cells



probably the result of a slowly inactivating Ca current and a decrease in outward K current that normally repolarizes

triggered activity

action potentials can trigger abnormal depolarizations that result in extra heart beats or rapid arrhythmias



this can occur when the first AP leads to oscillation of the membrane voltage - Afterdepolarizations

2 types of after depolarizations

early


occur during repolarization phase



delayed


occur shortly after repolarization has been completed



either way, abnormal APs are triggered if the afterdepolarization reaches threshold voltage

Early after depolarization

Delayed after depolarization

repetitive afterdepolarizations (like in an EAD) may produce...

rapid sequence of APs and a tachyarrhythmia

DAD may trigger

a propagated AP

Early after depolarizations

changes of membrane potential int he positive direction that interrupt normal repolarization



can occur during plateau of AP (phase 2)


or during rapid repolarization (phase 3)



more likely to develop in conditions that prolong AP duration (longer QT interval conditions)



appear to be the initiating mechanism of torsades

Delayed after depolarizations

most common occur in states of high intracellular calcium like dig intoxication



can lead to tachyarrhythmias



some idiopathic ventricular tachycardias and atrial and ventricular tachycardias associated with dig toxicity

conduction block

a propagation impulse is blocked when it reaches a region of the heart that is electrically unexcitable



can be transient or permanent



block can be unidirectional or bidirectional


functional block

occurs because a propagating impulse encounters cardiac cells that are still refractory from a previous depolarization



a pulse that arrives later might be conducted

fixed block

caused by a barrier imposed by fibrosis or scarring that replaces myocytes

AV block

conduction block within AV node or His purkinje system



prevents normal propagation of cardiac impulse from the sinuse node to more distal sites



removes the normal suppression that ikeeps latent pacemakers in the his-purkinje system in check


av block usualy results in the emergence of

escape beats/rhythms, as more distal sites assume pacemaker function

Re entry

an electric impulse circulates repeatedly around a re entry path, recurrently depolarizing a region of cardiac tissue

2 critical conditions for re entry

unidirectional block



slowed conduction through the re entry path

re entry



NORMALLY

the AP propagates in a way that prevents re entry



refractory periods keep any circular paths from being accessible in the wrong direction

unidirectional block and re entry

blocked region prevents normal propagation



normally, at certain junctions cells would be in a refractory period, but since the block was there, the cells are able to accept the AP in the wrong direction



unidirectional block and re entry tends to occur in regions

where the rafractory periosd of adjacent cells are heterogeneous



can also occur when cells are dysfunctional or fibrosis has altered the myocardial structure

unidirectional block and re entry



at normal retrograde conduction velocity

eventuallly when the signal goes around the re entry loop, it will still hit a point that is still refractory and stop

unidirectional block and re entry



slowed retrograde conduction velocity

by the time it gets to the spot past the initial blockage, refractory period is over



this can continue indefinitely and each pass through the loop excites cells of the distal conduction tissue which propagates to the rest of the myocardium at an abnormally high rate



tachyarrhythmia

mechanisms of arrhythmia development


bradyarrhythmias


altered impulse formation



decreased automaticity

decreased phase 4 depolarization


e.g. parasympathetic stimulation



sinus bradycardia

mechanisms of arrhythmia development


bradyarrhythmias



altered impulse conduction



conduction blocks

ischemic, anatomic, or drug induced impaired conduction



1st, 2nd, 3rd degree AV blocks

mechanisms of arrhythmia development


tachyarrhythmias



altered impulse formation



enhanced automaticity



sinus node

increased phase 4 depolarization



e.g. sympathetic stimulation



sinus tachycardia

mechanisms of arrhythmia development



altered impulse formation



enhanced automaticity



AV node

increaed phase 4 depolarization



e.g. sympathetic stimulation



AV junctional tachycardia

mechanisms of arrhythmia development



altered impulse formation



enhanced automaticity



ectopic focus

acquires phase 4 depolarization



ectopic atrial tachycardia and some forms of VT

mechanisms of arrhythmia development


altered impulse formation



triggered activity



EAD

prolonged AP duration



torsades de pointes

mechanisms of arrhythmia development



triggered activity



DAD

intracellular calcium overload



e.g. dig toxicity



APBs, VPBs, digitialis induced arrhythmias, idiopathic VT

mechanisms of arrhythmia development


altered impulse conduction



re entry



anatomical

unidirectional block and slowed conduction



atrial flutter


AV nodal re entrant tachycardia


VT related to ventricular scar tissue

mechanisms of arrhythmia development



re entry



functional

unidirectional block and slowed conduction



a fib


polymorphic VT


v fib

bradyarrhythmias


pharmacologic therapy


anticholinergic drugs

vagal stimulation: reduces rate of sinus node depolarization (slows HR) and decreases conduction through the AV node



so anticholinergics competitively bind to the Mu receptors that ACh binds to, and reduces vagal effect



results in increased HR and enhanced AV nodal conduction

bradyarrhythmias


pharmacologic therapy



beta receptor agonists

mimics the effect of endogenous catecholamines



increase HR


speed up AV node conduction

bradyarrhythmias


pacemakers

initiate depolarization at a desired rate


assume control of rhythm

tachyarrhythmias


pharmacologic therapy


desired drug effects to eliminate rhythms caused by increased automaticity

reduce the slope of phase 4 spontaneous depolarization of the automatic cells



make the diastolic potential more negative (hyperpolarize)



make threshold potential less negative

tachyarrhythmias


pharmacologic therapy



desired antiarrhythmic effects to interrupt re entrant circuits

decrease conduction in the re entry circuit to the point htat conduction fayils, thus stopping re entry impulse



increase the refractory period within the re entrant circuit so that a propagating impulse finds tissue within the loop unexcitable and the impulse stops



suppress premature beats that can initiate re entry

tachyarrhythmias


pharmacologic therapy



desired drug effects to eliminate triggered activity

shorten AP duration to prevent EADs



correct conditions of calcium overload to prevent DADs

arrhythmia drugs:


vaughn-williams classification



class I

predominantly Na channel blockers

arrhythmia drugs:


vaughn-williams classification



class II

beta adrenergic receptor blockers

arrhythmia drugs:


vaughn-williams classification



class III

predominantly K channel blockers

arrhythmia drugs:


vaughn-williams classification



class IV

non dihydropyridine Ca channel blockers

arrhythmia drugs:


vaughn-williams classification



class V

misc drugs (adenosine, dig)

Class I drugs effect on working myocytes



order of strength of effect

IC > IA > IB

Class I drugs effect on working myocytes



class IA

slows conduction


decreases I(Na)


smaller slope of



prolongs Action Potential Duration


decreases I(k)


prolongs QTc interval


Class I drugs effect on working myocytes



example-s of class IA drugs

procainamide


quinidine


disopyramide

Class I drugs effect on working myocytes



effects of IB drugs

mild conduction slowing


decreases I(Na)


decreases slope of upstroke



shortens action potential duration


decreases I(Na) and I(L)


shortens QTc interval

Class I drugs effect on working myocytes



examples of IB drugs

Lidocaine



mexilitine

Class I drugs effect on working myocytes



IC effects

slows conduction a LOT


decreases I(Na)


really decreases slope of upstroke



minimal effect on Action Potential Duration


QT lengthens, but only because QRS lengthens



action potential duration doesn't really change

Use dependency?


Class IC > IA drugs

binding to open/inactivated Na channels



plus



slow association/dissociation kinetics



means that more channels are blocked at faster heart rates



that's why these drugs are effective at terminating arrhythmias

Class IA clinical uses

atrial fib



atrial flutter



supraventricular tachy



ventricular tachy

class IA


quinidine

anticholinergic (moderate)



side effects:


cinchoism (blurred vision, tinnitus, headache, psychosis)


cramping and nausea


enhances dig toxicity

class IA


procainamide

anticholinergic (weak)


short half life



side effects:


lupus like syndrome

class IA


disopyramide

anticholinergic (strong)



side effects:


negative inotropic effect

Class IB clinical uses

ventricular tachy



dig induced ventricular arrhythmias

class IB



lidocaine

IV only; V tachys and premature ventricular contractions



side effects


good efficacy in ischemic myocardium

class IB



mexiletine

orally active lidocaine analog



side fx


good efficacy in ischemic myocardium

class IC clinical uses

a fib


a fluttter


supraventricular tachy (SVT)

class IC


flecainide

supreventricular tachy



side fx


can induce life threatening ventricular tachy

class IC


propafenone

supraventricular tachy



ventricular tachy



side fx


beta blocking and calcium channel blocking activity can worsen heart failure

class IA: Procainamide


indications

conversion of supraventricular tachy



pre excited a fib



a fib/a flutter



ventricular tachy

class IA: procainamide


mechanism

blocks I(Na)


depresses phase 0 - slows conduction



moderate K channel blocking activity prolongs Action Potential duration

Class IA: procainamide


metabolism

liver acetylation into NAPA



other 50-60 percent renally excreted



NAPA metabolite is 100 percent renally cleared


has Class III activity as a K cahnnel blocker (markedly prolongs repolarization)



need to watch NAPA levels which are different from procainamide levels

Class IB: Lidocaine


indications

ischemic ventricular tachy



dig induced arrhythmias (delayed after depolarizations)

class IB: Lidocaine


mechanism

blocks open/inactivated state of Na channel



rapid on/off kinetics



more active in tachy arrhythmias and in depolarized tissues (ischemic)



no effect on atrial tissue because of their short action potential duration

class IB: Lidocaine


clearance

hepatic


more toxicity with hepatic congestion (congestive heart failure)



monitor serum levels to minimize toxic effects

class IB: lidocaine


side fx

mainly CNS: confusion, paresthesias, dizzy, seizures

class IC: Propafenone


indications

SVT


AFib


Aflutter

class IC: propafenone


mechanisms

binds open state of Na channels



slow on.off kinetics



use dependency - more activity with faster heart rates


good for svt arrhythmia conversion


bad for scar-related, reentrant vt



can make vt incessant



has beta blocking activity like propanolol

class IC: propafenone


metabolism

hepatic -> hydroxypropafenone



parent propafenone has more beta blocking effect



7% are poor metabolizers that have more parent propafenone and an increased beta blocker effect

class IC: propafenone


contraindication

coronary disease or LV dysfunction/.structural heart disease



class IC: propafenone


side fx

cardiac - may precipitate ventricular arrhythmias and congestive heart failure



cns - dizziness, taste disturbance


class IC: propafenone


other

can organize afib to slower flutter allowing for 1:1 av nodal conduction

class II: beta blockers



indications

SVT



AFib/AFlutter rate control



VT



Long QT patients

class II: beta blockers



mechanisms

beta 1 receptor blockade reduces cAMP production



reduces PKA activity



reduces cytosolic Ca in myocardial tissue



decreases the slope of phase 4 in upstroke in nodal tissue



prolongs conduction time and refractoriness of nodal tissue

class II: beta blockers


side fx

bradycardia



bronchospasm



fatigue



depression



erectile dysfunction



weight gain



hyperglycemia



insomnia

class III drugsdo what...?

block K currents


I(Kr) I(Ks) I(K1)



pure I(Kr) blocker - dofetilide



beta blocking activity - sotalol: 1:1 d,l-isomers (d has no beta blocking activity)



enhances delayed inward Na current - ibutilide



IB, II, IV activity - amiodarone



like amiodarone but lacks iodine moiety - dronedarone

class III: amiodarone


indications

svt



af/avl



vt



vf

class III: amiodarone



mechanism

blocks


I(K)


I(Na)


I(Ca)



also has Class II effect

class III: amiodarone


metabolism

liver


half life ~ 100 days

class III: amiodarone


side fx

thyroid, pulmonary, hpeatic, ocular, neurologic, renal



proarrhythmia Torsades - very rare



numerus drug drug interactions - raises warfarin levels

Class IV: Ca channel blockers


nondihydropyridine

verapamil


dilitazem




slowed rise of action potential


prolonged repolarization at AV node



increase threshold potential of SA node


decrease heart rate



decrease conduction velocity of AV node and increase effective refractory period of AV node


decrease re entry and


decrease av node conduction

class effect on EKG


IA

PR 0


QRS increase


QT increase

class effect on ekg


IB

PR 0


QRS 0


QT 0 or decrease

class effect on EKG


IC

PR increase


QRS incraese


QT 0 or increase

class effect on EKG


II

PR 0 or increase


QRS 0


QT 0

class effect on EKG


III

PR 0 or increase


QRS 0 or increase


QT incrase

class effect on ekg


IV

PR increase


QRS 0


QT 0

class V


Dig


indications

svt



rate contrial for a fib

class v


dig


mechanisms

blocks Na/K ATPase which leads to inhibition of Na/Ca exchange, increasing intracellular Ca



vagomimmetic effect

class v


dig


clearance

renal excretion



half life of 36 to 48 hrs with normal renal function


3 to 5 days in anuric pts

class v


dig


side effects and toxicity

GI sypmtoms: loss of appetite, nausea, vomit, diarrhea



visual: yellow green halos and problems with colors



neuro: confusion, drowsy, dizzy, sleep disturbed, depression



cardiac: increased delayed after depolarizations. APC, VPC, paroxysmal atrial tachy with av block is pathognomonic for dig toxicity, vt or vf, heart block

class v


adenosine


indication

svt termination and diagnosis


class v


adenosine


mechanism

adenosine 1 receptor of av node



stimulates G(i) g proteins to decrease cAMP



increase K efflux and hyperpolarization



decrease Ca channel open probability



decrease I(f)


class v


adenosine


metabolism

adenosine deaminase in RBCs


half life ~ 10 sec


dipyridamole blocks adenosine deaminase

class v


adenosine


side fx

flushing


heart block


bronchoconstriction


headache


class v


adenosine


other

shortens action potential duration



potentiates Afib induction

class v


adenosine


contraindications

afib and wolf parkinson white syndrome: may incrase accessory pathway conduction



asthma - bronchospasms



cardiac transplants - exaggerated responses

class v adenosine


antagonists

methylxanthines-caffeine, theophylline

common arrhythmias in SA node



bradyarrhythmia

sinus bradycardia



sick sinus syndrom

common arrhythmias in SA node



tachyarrhythmias

sinus tachycardia

common arrhythmias in atria



bradyarrhythmias

none

common arrhythmias in atria



tachyarrhythmia

atrial premature beats (APBs)



atrial flutter



atrial fibrillation



paroxysomal supraventricular tachyarrhythmia



focal atrial tachycardia



multifocal atrial tachycardia

common arrhythmias in AV node



bradyarrhythmia

conduction blocks



junctional escape rhythm

common arrhythmias in av node



tachyarrhythmia

paroxysomal reentrant tachycardia (av or av nodal)

common arrhythmias in ventricles



bradyarrthymia

ventricular escape rhythm

common arrhythmias in ventricles



tachyarrhythmias

ventricular premature beats



ventricular tachy



torsades de pointes



ventricular fibrillation

sick sinus syndrom general

intrinsic SA node dysfunction that causes periosd of inappropriate bradycardia

sick sinus syndrome symptoms

dizziness



confusion



syncope

sick sinus syndrome treatment

IV anticholinergics (atropine)



beta adrenergics



if chronic, a pacemaker is requirede

elderly patients with SSS are also susceptible to

SVTs and Afib



this combination = bradycardia-tachycardia syndrome

Escape rhythms

cells in the av node and his purkinje system are capable of automaticity like the sa node, but usually have slower firing rates so they don't take over



if sa node becomes impaired or if there's some kind of conduction block, escape rhythm can emerge from the more distal latent pacemakers

junctional escape rhythm

arise from the av node or bundle of his



characterized by a normal, narrow QRS complex



occur in sequence



appear at a rate of 40-60 bpm

EKG of junctional escape rhythm

qrs complexes are NOT preceeded by normal p waves because the impulse originates below the atria



retrograde p waves can be observed as an impulse propagates from distal pacemakers up to the atria



these p waves typically follow the QRS and are inverted


inverted retrograde p waves in jucntion escape rhythm

negative deflection in leads II, III, aVF



indicating activation of the atria from the inferior direction

ventricular escape rhythms

even slower



30-40 bpm



widened qrs

why widened qrs in ventricular escape rhythms?

complexes are wide because the ventricles are not depolarized by the normal rapid simultaneous conduction of the right and left bundle branches



instead, from a more distal point in the conduction system

EKG of ventricular escape rhythms

qrs morphology depends on the site of the origin of the escape rhythm



originating from the left bundle branch will cause a right bundle branch block pattern



originating form the right bundle branch will cause a left bundle branch block pattern

why do we have junctional and ventricular escape rhythms?

they're protective backup mechanisms that maintain a heart rate and cardiac output when the sinus node or normal av conduction fails


treatment of escape rhythms

IV anticholinergics



beta adrenergics



pacemakers if chronic

av conduction system is made up of

av node



bundle of his



left and right bundle branches

what leads to av block

impaired conduction between the atria and ventricles

1st degree av block

prolongation of the normal delay between atrial and ventricular polarization



the impariment is usually within the av node itself and can be caused by a transient reversible influence or a structural defect

1st degree av block ekg

pr interval is lengthend to >5 small boxes



1:1 P:R ratio is maintained

reversible causes of av block

heightened vagal tone



transient av node ischemia



drugs that depress conduction through the av node like:


beta blockers


some ca channel antagonists


digitalis


other antiarrhythmics

structural causes of av block

MI



chronic degenerative diseases

1st degree av block treatment

usually benign and asymptomatic



requires no treatment

2nd degree av block

characterized by intermittent failure of av conduction


2nd degree av block ekg

some p waves not followed by qrs complexes

2nd degree av block



mobitz type 1



wenkebach block

degree of av delay gradually increases with each beat until an impulse is completely blocked



almost always results form impaired conduction in the av node

2nd degree av block



mobits type 1



wenkebach block



ekg

a qrs does not follow a p for one beat



you see a progressive increase in PR interval until a single qrs is absent



then PR goes back to initial length and the cycle starts over

2nd degree av block



mobitz type 1



wenkebach block



treatment

usually benign



treatment is typically not necessary



in symptomatic cases administration of atropine or isoproterenol improves av conduction transiently



permanent pacemaker required for symptomatic block that does not resolve spontaneously

2nd degree av block



mobitz type 2


sudden intermittent loss of av conduction without preceeding gradual lengthening of the PR interval



usually caused by a block beyond the AV node in the bundle of his or purkinje system

2nd degree av block



mobitz type 2



ekg

PR interval isn't changing but a qrs just gets dropped



may persist for 2 or more beats


multiple Ps are NOT followed by QRSs


known as high grade av block



qrs is often widened in a pattern like right or left bundle branch block

2nd degree av block



mobitz type 2



treatment

more dangerous than type I and treatment with a pacemaker is usualy warranted, even in asymptomatic patients

3rd degree av block

complete heart block



presenet when there is complete failure of conduction between the atria and ventricles



electrically disconnects the atria and ventricles



atria depolarize in response to SA node


more distal escape rhythm drives the ventricles independently



caused by MI or chronic degeneration

3rd degree av block



ekg

no relationship between p waves and qrs complexes



p wave rate is not related to qrs intervals

3rd degree av block treatments

permanent pacemaker is almost always necessary

tachyarrhythmias

when HR is > 100bpm for 3 beats or more



results from:


enhances automaticity


re entry


triggered activity

supraventricular tachyarrhythmia (SVT)

arises above the ventricles

ventricular tachyarrhythmia

arises from within the ventricles

SVTs



sinus tachycardia

sa node discharge rate >100bpm



normal p waves and normal qrs complexes



usually results from increased sympathetic or decreased vagal tone

SVTs



atrial premature beats

originate from automaticity or re entry in an atrial focus outside the SA node



often exacerbated by sympathetic tone

SVTs



atrial premature beats (APBs)



ekg

appears as earlier-than-expected p wave with an abnormal shape



qrs is usuallly normal. if they're wide, it's apb with aberrant conduction

SVTs


atrial premature beats (APBs)


treatment

only req treatment if they're symptomatic



caffeine, alcohole, stress can predispose to APB



beta blockers are the initial preferred treatment

SVTs



Atrial flutter

rapid, regular atrial activity at a rate of 180-350 bpm



many of these impulses reach AV node during refractory period and dont conduct to the ventricles

SVTs



atrial flutter



example of 2:1 block

300bpm at atria



150 bpm at ventricles



SVTs



atrial flutter



ekg

p waves have a sawtooth appearance



faster rates (>100bpm) cause palpitations, dyspnea, weakness

SVTs



atrial flutter



treatment

vagal maneuvers like the carotid sinus massage decrease AV conduction and further lower ventricular rate



antiarrhythmics that reduce the rate of atrial flutter can be dangerous because they allow the av node more time to recover between impulses.



AV node may begin to conduct 1:1


atria could be 280bpm w/ 2:1 block, 140 bpm ventricles



if the atrial rate slows to 220bpm, the ventricle rate could accelerate to 220bpm

SVTs



atrial flutter



treatment, drugs etc

electrical cardioversion to restore sinus rhythm



rapid atrial pacing w pacemaker



beta blocker, ca channel blocker, or digitalis to slow ventricular rate



then restore sinus rhythm with antiarrhythmics that slow conduction or prolong refractory period (class IA, IC, III)



catheter ablation

SVTs



atrial fibrillation

chaotic rhythm with atrial rate so fast that distinct p waves are not discernible on ECG (350-600 discharges/min)



avg ventricular rate in untreated A Fib is 140-160 bpm



mechanism probably involves multiple wnadering re entrant circuits within the atria

SVTs



atrial fibrillation



ekg

irregularly irregular rhythm



ecg baseline shows low amplitude undulations puncutated by QRS complexes and T waves


SVTs



atrial fibrillation



symptoms and signs

Afib is often associated with enlarged L or R atrium



heart failure, hypertension, coronary artery disease, pulmonary disease


^^^all promote AFib because they promote atrial enlargement

why is a fib so bad?

rapid ventricular rates may compromise cardiac output leading to hypotension and pulmonary congestion



absence of organized atrial contraction promotes blood stasis in atria, increasing risk of thrombus formation, especially in left atrial appendage

SVTs



afib



treatment considers 3 things

ventricular rate control



methods to restor esinus rhythm



assessment of the need for anticoagulation to prevent thromboembollism

SVTs


afib



drug treatment

similar to Atrial Flutter



beta blockers and calcium channel antagonists promote block in av node and reduce ventricular rate



digitalis is less effective



class IA, IC, III antiarrhythmics are used to restore sinus rhtyhm


^^have bad side fx so they're not used in asymptomatic patients



AFib for more than 48 hours needs anticoagulation



MAZE procedure and catheter ablation are alternatives to antiarrhythmics



catheter ablation can be used to induce complete AV block and slow ventricular rate. a permanent pacemaker is needed after this

SVTs



Paroxysmal supraventricular tachycardias (PSVTs)

sudden onset and termination


atrial rates between 140 and 250 bpm



narrow (normal) qrs complexes



mechanism is most often re entry involving AV node, atrium, or an accessory pathway



enhanced automaticity and triggered activity in the atrium or AV node are less common causes

SVTs


PSVTs



AV Nodal Re Entrant Tachycardia (AVNRT)

most common form of PSVT in adults



there can be multiple potential pathways through the AV node and they can conduct at different velocities



the slower pathway usually has a shorter refractory period

SVTs



PSVTs



AVNRT pathway

Atrial premature beat travels to the junction between slow and fast pathways


conducts down slow pathway since it has a shorter refractory period and already repolarized



by the time it gets to the compact portion of the AV node, the distal end of the fast pathway has repolarized and the signal can go distal to the bundle of his AND backwards up the fast pathway toward the atrium



at the top of the fast pathway it comes back down thte slow pathway = loop

SVTs


PSVTs



AVNRT



EKG

ecg shows a regular tachycardia with normal width QRS



retrograde p waves usually get hidden in QRS but they can sometimes be seen at the terminal portion of QRS complex



they'l be inverted in leads II, III, aVF since the atrial activation is going "up"

SVTs


PSVTs


AVNRT


symptoms and signs

usually tolerable with just palpitations



rapid tachycardias can cause lightheadedness or shortness of breath



elder patients can get syncope, angina, pulmonary edema

SVTs


PSVTs


AVNRT



treatment

acute


terminate re entry by imparing conduction in AV node


valsalva maneuver or carotid sinus massage may block AV conduction and terminate the tachycardia



pharmacologic


IV adenosine impairs AV nodal conduction and aborts re entrant rhythm


other options= beta blockers and calcium channel antagonists



catheter ablation or class IA, IC antiarrhythmics might be used for chronic problems with AVNRT

SVTs



Atrioventricular Re entrant Tachycardias (AVRTs)

similar to AVNRTs except one limb of the loop is made up of an accessory tract instead of 2 separate slow and fast pathways through the AV node

accessory tract

bypass tract


an abnormal band of myocytes that spans the AV groove and connects atrial to ventricular tissues separately from the normal conduction system

Ventricular pre-excitation syndrome


Wolff Parkinson White syndrome

atrial impulses can pass in an anterograde direction to the ventricles through both the av node and the accessory pathway



conduction through the accessory pathway is usually faster than that via the AV node



ventricles are stimulated earlier than by normal conduction over the AV node

Ventricular pre excitation syndrome


WPW syndrome



ekg

during sinus rhythm:


PR interval is short because ventricular stimulation starts earlier than normal



QRS has a slurred, rather than sharp, upstroke (delta wave) because the accessory pathway activates the ventricle slower than the purkinje system



QRS is widened because it represents the fusion of 2 events (conduction through both pathways)

ventricular pre excitation syndrome


WPW syndrome


treatment

pharmacologic management



have to be more careful than with AVNRT patients



beta blockers, calcium channel antagonists, and digitalis all can block condcution through the av node but they do not slow conduction over the accessory pathways

Common ventricular arrhythmias

VPBs


VT


VFib

Ventricular premature beats (VPBs)

similar to APBs, VPBs are common and often asyptomatic and benign



a VPB arises when an ectopic ventricular focus fires an action potential

VPBs



ekg

appears as a widened QRS complex because the impulse travles from its ectopic site through the ventricles via slow cell to cell connections rather than the faster his-purkinje system

VPBs



treatment

in healthy patients, treatment is reassurance and symptomatic use of beta blockers



if patients have advanced structural heart disease with features that place them at risk for life-threatening arrhythmias, placement of an inflatable cardioverter defibrillator (ICD) is recommended

Ventricular Tachycardia

series of 3 or more VPBs

sustained VT

persists more than 30 sec



produces sever symptoms like syncope


or


requires termination by cardioversion or administration of a drug

unsustained VT

self terminating episodes

VT EKG

qrs complexes are wide (>0.12sec)


100-200 bpm


monomorphic VT

QRS complexes all look the same and rate is regular

polymorphic VT

qrs complexes change in shape and rate varies

symptoms of VT

vary depending on the rate, duration, underlying condition



sustained VT can cause low cardiac output leading to syncope


pulmonary edema


cardiac arriest



but if it's slow (<130bpm) it might only cause palpitations

distinguishing monomorphic vt from supraventricular tachycardia

width of the qrs complex



monomorphic vt = wide



svt = narrow (normal) unless SVT with aberrant ventricular conduction



SVT with aberrant conduction occurs in:

patients with underlying conduction abnormality like a bundle branch block



repetitive rapid ventricular stimulation durign SVT finds one of the bundle branches refractory



pt develops antidromic tachy through an accessory pathway

managing patients with VT

acute treatment = cardioversion


iv administration of antiarrhtyhmics, procainamide/lidocaine



after sinus rhythm is restored: determine whetehr underlying heart disease exists



correct aggravating factors like:
myocardial ischemia


electrolyte disturbances


drug toxicities



beta blockers, calcium channel blockers, catheter ablation are commonly effective to control symptomatic episodes of idiopathic VT

torsades de pointes

a polymorphic VT that presents as varying amplitude of QRS



can be produced by EADs (triggered activity) particularly in patients with prolonged QT intervals

torsades symptomes

light headed



syncope



main danger is from degeneration into VFibt

torsades treatment

when it's drug or electrolyte induced, correcting the underlying cause abolishes recurrences



in other cases, administration of IV magnesium represses episodes



also: shorten QT intervals via beta adrenergic stimulating agents or an artificial pacemaker



if torsades is because of a congenital prolongation of QT, beta blockers are preferred


sympathetic stimulation aggravetes the arrhythmia in many such individuals

ventricular fibrillation

immediately life threatening



results in disordered, rapid stimulation of the ventricle with no coordinated contractions



result = no cardiac output and death if not quickly reversed



VF is often initiated by an episode of VT that degenerates into multiple smaller wavelets of re entry that wander the myuocardium

Ventricular feibrillation



treatment

only effective therapy is prompt electrical defibrillation



after the heart has been converted to a safe rhythm, correct underlying issues:


electrolyte imbalances, hypoxemia, acidosis



IV antiarrhythmics can be administered to prevent immediate recurrences

inherited arrhythmogenic disease



familial arrhythmia

monogenic diseases with mendelian inheritance



conditions include:


channelopathies


cardiomyopathies


ion channels proteins


muscle proteins

IAD


channelopathies

long qt syndrome



short qt syndrome



brugada syndrome



catecholaminergic vt



idiopathic vt/vf

IAD


cardiomyopathies

dilated



hypertrophic



arrhythmogenic RV/LV



restrictive



non compaction

background of IADs

relative rare -> 1:500 to 1:10000



young people [childhood -> midlife]



high risk of sudden cardiac arrest/arrhythmia

3 representative examples of genetic mutations leading to arrhythmias

long qt syndrome



brugada syndrome



hypertrophic cardiomyopathy

where to you measure the QT interval?

lead II or V5

Long QT Syndrome 1


LQTS1

k current



decreases



mostly exercise triggered

Long QT Syndrome 2


LQTS2

k current



decreases



mostly emotional stress triggered

Long QT Syndrome 3


LQTS3

Na current



increases



mostly triggered during sleep/repose

LQTS2



HERG channel

hERG channel makes the alpha subunit of the k channel that does the I(kr) current



conducts K out of the cell to make repolarization happen



if it's blocked or doesn't correctly undergo conformational changes, it can be deficient in the amount of K it pumps out



pumping out K less effectively can prolong the repolarization phase of a cardiac myocyte's action potential

LQTS risk by QTc

there is stratification among the quaqrtiles



the shortest QTs (closest to normal) are associated with better survival than the longer QTs

LQTS mechanisms

abnormal impulse can lead to triggered event



DAD reaches threshold and fires off in a triggered way



EAD can trigger arrhythmia

LQTS treatment

beta blockers



work best for LQT1


then LQT2


then LQT3

Brugada syndrome

right bundle branch block and ST segment elevation in leads V1, V2, V3



a marker for sudden death in patients without demonstrable structural heart disease

brugada syndrome ekg

ST segment elevation and what looks like RBBB but it's "coved" or elongated/wide



especially in v2



the ekg is really dynamic though. it can change through out the day,

brugada symptoms

cluster by age


most abundant in 31-40 year olds and 41-50 year olds



SCN5A

the Na channel messed up in brugada



has three states: resting, open, inactivated



resting state is closed compoletely



depolarization causes it to open up and Na can come into the cell



eventually it inactivates. It stays open but it's plugged on the cytosolic end. This plug is responsible for the refractory period



once inactivated the channel needs repolarization to reactivate

phenotypic heterogeneity in brugada

different presentations from the same channel



coving of the QRS can be highlly variable from pt to pt

what is this notch

what is this notch

the I(to) current activates at phase 1 and pumps K out, but the balancing action of Na in is defective, so membrane potential gets negative more quickly than usual, without the gradual plateau

brugada causes a gradient between what?

between endocardium and epicardium



the epicardium is the one that has the deeper notch. the endocardium looks relatively less affected.

brugada re entry

endocardium and epicardium fire cardiac action potentials but the epicardium ap collapses



an early afterdepolarization fires off and stimulates another part of the Epi. that part fires backwards to the first part of epi and then back up to the endocardium

brugada treatment

quinidine



catheter ablation



whatever you do, the most important thing is to prevent the v fib in the first place

mutations in hypertrophic cardiomyopathy



just about anythign int he cardiac sarcomere



troposin I, troponin T, tropomyosin, actin

pathologic elements to HOCM

LVOT obstruction



impaired disatology



Mitral regurg/papillary muscle displacement



ischemia



dysautonomia

treatable at all levels

for sudden death: ICD



for progressive heart failure: drugs, myectomy



for end stage: transplant



for AFib and stroke: drugs like warfarin

relation between LV wall thickness and sudden death

incidence of sudden death rises with LV wall thickness



above 30 milimeters there's a super high risk

myectomy

scrape out the thick portion of the septum



increases survival


prior cardiac arrest or sustained vt

ICD recommended

family history - SD in first degree relative


or LV wall thickness >30 mm



or recent unexplained syncope

ICD reasonable

nonsustained VT



abnormal BP response

ICD can be useful if there's



LVOT obstruction


LGE+


LV apical aneurysm


genetics

alcohol and caffeine causing arrhythmias

caffeine can release norepi



heavy drinking can make you lose elctrolytes(?)

what does it tell you if an arrhythmia is or isn't exercise induce?

if it's not exercise induced then it's probably not related to a coronoary problem

what do diving into a swimming pool or defecation do to help alleviate arrhythmia?

induce vagal tone



if this works, it implies that the arrhythmia is related to the AV node



you wouldn't expect a ventricular arrhythmia to respond to vagal toneh

hyp[ertension and diabetes with arrhythmia?

they're risk factors for heart diseasec

chest trauma with arrhythmia?

could be scarring

where do atrial premature beats come from

pulmonary veins

if atrial premature beat hits the right atrium

it can find its way into a pathway involving the whole thing:



IVC


SVC


tricuspid annulus


coronary sinus



leads to atrial flutter

p wave morphologies

p wave morphologies

first one is normal



second one implies the LA is enlarged



third one implies the RA is enlarged



a fib would be most likely if LA was enlarged

PR interval changes

if av node was diseased the PR interval would get longer



a shorter PR interval could occur if the AV node is getting bypassed

narrow complex tachycardia

implies it's going through the normal pathwayw

wide complex tachycardia

would imply that a different pathway is being used and that they tachy is ventricular

if you give a patient adenosine and it breaks the tachycardia

it means the tachycardia involves the AV node

what clinical and ecg features suggest a supraventricular etiology?

vagal maneuvers stop it



narrow qrs, preceded by p wave, looks "normal"

what is differential from a wide qrs tachy

svt with rbbb


hyperkalemia


wpw syndrome - delta waves

sudden on, sudden off in ekg suggests which mechanism for tachy

reentry

why are beta blockers successful in controlling this arrhythmia

beta blockers impair AV nodal conduction and there are exta-atrial beats

arrhythmia conference chart



sinus tachycardia

not dependent on av node



has organized atrial activity



regular rhythm but could warm up and cool down



gradual onset/offset

arrhythmia conference chart



atrial tachycardia


ectopic atrial focus

not dependent on av node



has organized atrial activity



regular



gradual onset/offset

arrhythmia conference chart



atrial fibrillation

not dependent on AV node (originates in pulmonary veins in LA)



no organized atrial activity



not regular



rapid onset/offset

arrhythmia conference chart



atrial flutter

not dependent on av node - caval tricuspid isthmus



has organized atrial activity (250-240ms) sawtooth waves



v1 has what look like p waves



could be regular or irregular



rapid onset/offset

arrhythmia conference chart



AVNRT

dependent on av node



organized atrial activity



regular



rapid onset/offset

arrhythmia conference chart


AVRT

dependent on av node activity and accessory pathway



organized atrial activity



regular



rapid onset/offset with delta wave

blood flow

actual volume of blood flowing through a vessel, organ, or the entire circulation in a given period



measured in ml/min



equivalent to cardiac output



relatively constant at rest



varies through individual organs according to immediate needs

which tissue has the most blood flow at rest?

kidneys

radial artery: inactive hand



high pulsatility waveforms are a feature of circulatory systems with high resistance to blood flow (High peripheral resistance)

radial artery: active hand



lower resistance to blood flow?

bernoulli's principle

as the speed of a moving fluid increases, the pressure within the fluid decreases



to keep the total energy the same, if velocity goes up, pressure has to go down

pressure and flow relationship

as stenosis severity increases, blood velocity increases to maintain flow



at 75% stenosis, flow begins to decrease and the pressure generated downstream decreases creating a pressure gradient

vascular physiology principles (3)

diastolic flow is important to maintain adequate tissue perfusion



an increase in blood velocity occurs at a stenosis



at 75% stenosis flow and pressure decrease

aneurysm definition

to widen or dilate



focal dilatation with at least 50% increase over normal arterial diameter



>3cm in abdominal aorta



1.8cm for iliac arteries



abdominal aortic aneurysm present in 6-9% of men over 65 years old in US

ascending aortic aneurysm

characterized by cystic medial degeneration


degeneration and fragmentation of elastic fibers, accumulation of collagenous and mucoid material within the medial layer



occurs most commonly with aging and hypertension



other causes:


marfan syndrome


loeys-dietz syndrome


ehlers danlos syndrome


bicuspid aortic valve


syphilis


vasculitis

abdominal aorta epidemiology



traditional risk factors

increasing age



smoking



male sex



genetic



screening for AAA in old men improves morbidity and mortality

CT scan of abdominal aortic aneurysm

at what diameter does rupture risk start for AAA

4-5 cm

aortic wall tension

pascal's principle requires that pressure is the same everywhere inside the balloon at equilibrium



but examination revelas that there are great differences in wall tension on different parts of an aortic aneurysm



variation is described by laplace's law - wall tension is proportional to the product of pressure and radius



pressure stays the same, radius goes up, so tension goes up - leading to rupture

AAA therapy

medical


smoking cessation


hypertension therapy like beta blockers, ace inhibitors, angiotensin receptor blockers



endovascular therapy


lower early risk -problems over time



open therapy


up front risk - better durability over time

Peripheral Artery disease - how many patients have symptoms

1 in 5 people over 65 has PAD



only 1 in 10 of these patients has classical symptoms of intermittent claudication (walking leading to pain. stopping and it gets better)

clinical presentations of peripheral artery disease

50% asymptomatic


33% atypical leg pain


15% classic claudication


1-2% critical limb ischemia (gangrene or pain at rest)

relationship between increased age and peripheral vascular disease

for PAD, once you reach 70 incidence exponentially goes up

ultrasound velocity signal in PAD

monophasic waveform



only see broad upstroke through all of systole, no diastolic backflow

normal vessel characteristics

laminar flow



endothelial cell mediated vasodilation



distal pressure and flow maintained

PAD vessel characteristics

high resistance



collateral vessel



turbulent flow



pressure drop across stenosis



impaired endothelial function



inability to increase flow with exercise

dx of PAD includes...

atherosclerosis



vasculitis



fibromuscular dysplasia



trauma



thrombotic disorders



vascular tumor

claudication

cramping, tightness, aching, fatigue




exercise induced



does not occur with standing



standing up relieves it



goes away in less than 5 minutes

pseudoclaudication

cramping, tightness, aching, fatigue, tingling, burning, numbness




variably induced by exercise



does occur with standing



sitting relieves it



takes 30 minutes to go away

PAD comprehensive vascular exam includes

pulse examination:


carotid


radial


brachial


femoral


pooliteal


dorsalis pedis


posterior tibial



physical exam:
bilateral arm blood pressure (is it the same in both arms)


cardiac exam


palpation of abdomen for potential aneurysm


auscultation for bruits


examination of lower extremities

measureing ankle brachial index ABI

pressure in ankle should be higher or the same, but not lower



take highest pressure in L and R ankles and divide by the highest arm pressure (whichever arm is highest)



anything above 0.91 is normal, below that is pathologic

exercise and leg pressure

should NOT have a drop in pressure when you exercise

ABI vs mortality

as ABI decreases, risk of mortality increases



but once you get to >1.4 you have incompressible arteries - different problem

PAD therapy


exercise

exercise does better than intervention

PAD medical therapy

smoking cessation



lipid modification - statins



HTN control



antiplatelets



diabetes control



foot care



risk factors



symptomatic relief - cliostazol and pentoxifylline

stroke - vision complaints?

opthalmic artery



one of the first early warning signs

hollenhorst plaque

you can see a cholesterol embolus in the retina from the internal carotid artery

carotid artery disease



medical therapy

antiplatelet therapy



anticoagulation



risk factor modification - smoking cessation, statins, HTN, diabetes control

arteriovenous malformations

defects in the vascular system



direct connections between arteries and veins



it is believed that they often result from mistakes during embryonic or fetal development



can happen anywhere but are most common in brain or spinal cord



greatest potential danger is hemorrhage



treated via surgery or focused irradiation

leading cause of death in the US

atherosclerosis

risk factors for coronary artery disease

herditary:


mutations and strong family history



homocyssteine


Lp(a)


Clotting and inflammatory factors



lipids:


increased LDL, decreased HDL, increased Tg



smoking



diabetes



HTN



obesity



sedentary lifestyle

hsCRP

baseline levels of the inflammation marker hsCRP in apparently healthy men can predict the riskk of first MI or ischemic stroke



aspirin reduced inflammation which is a component of athersclerosis

atheroma formation


stage 1

retention of Apo B lipoprotein


particles enter the tunica intima from the lumen and are retained

atheroma formation


stage 2

retained lipoprotein particles are likely modified (oxidized and aggregated)



intima gets larger, more lipid shows up

atheroma formation


stage 3

monocytes are attracted to the artery, which they enter and turn into macrophages



atheroma formation


stage 4

macrophages ingest retained lipoproteins


"foam cells" die and make fatty streak

atheroma formation


stage 5

other immune cells enter and area ctivated



inflammatory cytokines, chemokines, proteases, free radicals cause further tissue damage



cap between fatty and thrombogenic mess protects it from rupturing

hallmarks of defective inflammation resolution in atherosclerosis

persisten influx



defective egress



retained lipoproteins



necrosis



thinning of fibrous cap

thinning of fibrous cap

two processes:


synthesis involves Platelet derived growth factor and TGF-beta inducing smooth muscle cells + collagen and elastin to make the cap



degradation:


t lymphocytes release interferon gamma which inhibits the synthesis


and make cd40L which causes foam cells to release MMPs that degrade the matrix and thin the cap

rupture

when the cap gets too thin, the atheroma can rupture



when blood and fat mix a thrombus forms

endothelial dysfunction

chemical irritants and hemodynamic stress can cause dysfunction of the endothelium



lipoprotein entry, inflammatory cytokines



chemokines and leukocyte adhesion molecules



leykocyte recruitment



you can improve endothelial function by lowering blood pressure and dialyzing lipid



unregulated uptake of modified LDL



foam cell formation

2 major adverse consequences of endothelial dysfunction

increased recruitment of inflammatory cells



loss of NO mediated vasodilation

what does arginine do for vasorelaxation?

NO synthase makes NO out of arginine



NO can diffuse to smooth muscle cells and induce relaxation by increasing cGMP

atherosclerotic endothelium allowing vasoconstriction

there's a breakdown between the conversion of arginine to NO



instead of NO you make OONO (peroxy nintrates) preventing vasodilatory response

consequence of proximal obstruction

a region becomes inadequately perfused

angina pectoris

discomfort of thoracic cavity that comes on with exercise and goes away after

early atheroma can go two ways

stable plaque


small lipid pool


thick fibrous cap


preserved luman



vulnerable plaque


large lipid pool


thin fibrous cap


many inflammatory cells

vulnerable plaque

ruptures and forms thrombus



it can heal with a narrowed lumen and fibrous intima


or


you can get an acute MI

angina of two sorts

demand angina


comes on with exercise



resting angina - unstable


a plaque rupturing

therapeutic opportunities for plaque rupture

lower apoB lipoproteins



dampen inflammation and restore homeostasis



enhance efferocytosis and restore fibrous cap

atherosclerosis pathophysiology


stage 1

endothelial dysfunction



HDL prevents cell adhasion, LDL promotes cell adhesion



too much LDL and platelets and monocytes adhere to the vessel wall

atherosclerosis pathophysiology


stage 2

smooth muscle emigration from media to intima



macrophage activation



macrophages come from lumen


sm muscle comes from tunica media

atherosclerosis pathophysiology


stage 3

macrophages and smooth muscle cells engulf lipid



they get engorged and make a fatty streak

atherosclerosis pathophysiology


stage 4

smooth muscle proliferation



collagen and other ecm deposition



extracellular lipid



vessel wall becomes very full because of all the ECM junk



fibrofatty atheroma is visible

atherosclerosis


4 stages condensed

endothelial injury leads to dysfunction


adhesion of monocytes and platelets and lipid influx



migration of macrophages and smooth muscle cells into the intima



phagocytosis by macrophages and smooth muscle cells of lipids = fatty streaks



proliferation of SMCs and deposition of ECM: fibrofatty atheroma

TGF-beta

major role in fibrosis stage 4



an inhibitor of TGF-beta might inhibit atherosclerotic process

what's this?

what's this?

macrophages ldoaded with lipids

dangerous of fibroatheromas

increased demand can't get met because of blockage



in the plaque you can have a hemorrhage



intra plaque hemorhage can make plaque bigger and cause more occlusion



ultimately you can get a thrombus formation in the lumen

atherosclerosis complications

thrombosis



embolism



aneurysm and rupture



dissection

aneurysm definition

dilatatio of segment of vessel

true aneurysm

bulging because the whole lumen is bulging

false aneurysm

something in the vessel wall is causing the bulge, like an extravasation of blood

difference between fusiform and saccular aneurysms

you can't clip a fusiform aneurysm because the whole thing is bulging



you CAN and probably SHOULD clip a saccular aneurysm

aneurysm etiologies

atherosclerotic



infectious (syphilis)



inflammatory



autoimmune



degenerative



traumatic

aortic dissection

hole in the wall of the vessel



a small local dissection causes pain but a big one is fatal



entry point is an atheromatous lesion



a weak point that lets the blood flow get into the vessel

contributing factors to aortic dissection

aging



atherosclerosis



hypertension in 60-70 percent



marfan or ehlers danlos syndromes

type a dissection

proximal dissection with variable distal extension



ascending part is dissected


could occlude coronary arteries or carotid arteries and mess with perfusion to heart or brain



these patients need to go to the OR

type b dissection

distal dissection



tend to rupture into the left thorax



only the descending part is dissected



they usually need medical management

aortic dissection complications

external rupture: in 90 percent may be fatal



compression of origins of arteries


coronary


carotid


renal


mesenteric arteries

vasculitides



classify based on the type of blood vessel they affect

giant cell arteritis - lg vessels



polyarteritis nodosa - med vessels



wegener granulomatosis - small vessels



buerger's disease - mixed

giant cell arteritis

over 50y


headaches



palpable tender nodularity of artery



visual problems, blindness



ESR markedly elevated



polymyalgia rheumatica



steroid therapy

polyarteritis nodosa

young adults



acute, subacute, or chronic



rever, weight loss, abdominal pain, melena, muscular aches, peripheral neuritis



untreated, fatal, either during an acute fulminant attack or following a protracted course



corticosteroids - remission or cures in 90% of cases

polyarteritis nodosa

transmural inflammation (neutrophils, eosinophils, mononuclear cells)



fibrinoid necrosis



later, fibrousd thickening



all stages of activity may coexist in different vessels or even within the same vessel

wegener granulomatosis

males > females, 40 yo



syndromes similar to PAN and respiratory involvement



fever, persistent pneumonitis, chronic sinusitis



mucosal ulcerations o fthe nasopharynx



renal disease



skin rashes



muscle pain, joints, neuritis



eye, skin, and heart



untreated, aggressive course; 80% death

buerger's disease

more prevalent in young adult men smokers



immunologic and thrombogenic mechanisms



only smoking cessation stops disease activity

Deep veint thrombosis and pulmonary embolus

thromboembolism is seen in over 275000 americans annually



deep veinsof the calf



therapeutic emergency: heparin

risk factors for dvt

dehydration



prolonged bed rest



surgery



fractures of hip or femur



massive trauma



stroke



heart attack



cancer



oral contraceptives



childbirth

pulmonary embolus

often in hospitalized patients



shortness of breath, chest pain, syncope, hemoptysis



chest x ray, CT, pulmonary ventilation/perfusion scan, pulmonary angiogram

pulmonary embolus treatment and prognosis

thrombolytic and anticoagulant therapy



death rate - 30% if undiagnosed, 3% with early diagnosis and treatment



with large emboli mortality >50%

varicose veins

distended veins because valves cant keep the blood up

relationship between cholesterol and coronary heart disease risk

increase cholesterol, increase rate of death from heart disease

naturally occurring lipids and their functions

triglycerides - energy storage



cholesterol - important precursor of steroid synthesis



phospholipids - important components of cell membranes

lipoproteins

allow insoluble lipids to travel in blood



apolipoproteins are found on the surface and serve as ligands for cellular receptors

VLDL

in the liver

IDL

catabolism of VLDL

LDL

catobolism of IDL



bad cholesterol

HDL

liver, intestine, other



good cholesterol

bile salts

solubilize cholesterol coming from the liver

VLDL and LDL cholesterol transport

VLDL loses ApoC-II and becomes IDL



IDL loses ApoE and becomes LDL



LDL has ApoB-100 left and can enter muscle/heart/adipose tissue or participate in atherogenesis

prevention of atherosclerotic cardiovascular disease

primordial prevention


prevent the development of risk factors for CVD



primary prevention


prevent the first CVD event



secondary prevention


prevent subsequent CVD events

benefits of LDL reduction

lowering LDL may slow progression, stabilize, or reverse atherosclerosis



lowering LDL improves endothelial cell function



lowering LDL prevents MI and improves survival

Non HDL calculation

total cholesteral minus HDL cholesterol



this has shown to be a stronger predictor of cardiovascular risk than LDL cholesterol

treatment of dyslipidemia

diet and exercise!!



statins



intestinal acting cholesterol lowering agents like bile acid sequestrants and cholesterol absorption inhibitors



nicotinic acid



fibric acid derivatives



statins-HMGCoA reductase inhibitors



fish oil



new drugs for extremely high ldl



emerging classes - pcsk9


bile acids

breakdown product of cholesterol



40-70% reabsorbed in the small bowel



act as detergent - help - make cholesterol soluble

inhibition of bile acid reabsorption

bile acid sequestrants



cholestyramine


colestipol


colesevelam


^^aka WelChol - also lowers blood sugar (reduces Hba1c)i

nhibition of cholesterol absorption

selective cholesterol absorption inhibitors



ezetimibe

if you sequester bile salts

you cant solubilize cholester



cholesterol goes into stool



LDL goes down by 10 or 20 percent



BUT the liver makes more to "compensate" so it kind of buffers the effect in a bad way

remember about Welchol!

it lowers LDL AND blood sugar

bile acid binding resin side effects

bloating



may interfere with absorption of fat soluble vitamins



may interfere with absorption of digitalis, thiazides, warfarin, aspirin



can raise Tgs

Ezetimibe

localizes on the brush border of intestinal epithelial cells



circulates enterohepatically



well tolerated, no effect on vitamin absorption



long biological half life



used mainly as an add on to statins



decrease heart attack and stroke

ezetimibe + statin

wayyy lower LDL levels, even better than with just statin



also lowers event rate percentage

nicotinic acid

decreases vldl production



decreases ldl formation and increases hepatic clearance of LDL precursors



raises HDL levels



lowers Lp(a) levels


^^^particle that has been linked to clots

nicotinic acid


niacin

check liver transaminases, glucose levels, lipid levels, and uric acid levels



used infrequently today



was negative for reducing cardiovascular events

niacin side fx

intense flushing and pruritis



hepatic toxicity - increasing transaminases



glucose intolerance (raises blood sugar)



elevate uric acid levels



contraindicated in patients with gout



dont give niacin to patients with gout!!!

fibrates

lower trigylcerides by 35-50 percent


barely lower ldl ata ll



raises HDL a little



most useful in pts with elevated triglycerides or low HDL



should be avoided in pateitns with hepatic or renal dysfunction



caution with patients on statins - increases risk of rhabdomyolysis


use fenofibrate if you have to add fibrate to statin

gemfibrozil

fibrate



slight increase in HDL



decent degrease in TG



no change in LDL

fenofibrate

fibrate



indicated for severe hypertriglyceridemia


pts at risk for pancreatitis



safer than other fibrates when used with a statin



cna elevate creatinine (kidney function)


fibrate evidence

on background statin Rx, fibrate does not reduce CV events

fish oil treatment

used to lower high TGs


efficacy depends on baseline TGs



FDA approved versions for pts with baseline TG above 500



may increase ldl



can increase bleeding time and interact with warfarin!!!



often stopped prior to surgery

what does HMG-CoA reductase do

converts acetate to cholesterol

so an HMG-CoA reductase inhibitor...


(statins)

lowers cholesterol synthesis

statins and diet

statins reduce cholesterol production


NOT ABSORPTION



doesn't do anything to the choelsterol you eat, just the cholesterol you make

statin side fx

elevations in transaminases



hepatix toxicity related to ^^ if too much



myositis presenting as muscle pain or weakness with elevated muscle enzyme levels



recent link to increased risk of diabetes (HgA1C goes up)



can affect memory

statin therapy recommended in 4 groups(!!!)

adults with clinical ASCVD (heart diseae)



adults with LDL >190 mg/dL



adults 40 to 75 years old with diabetes



adults >7.5% estimated 10 year risk of ASCVD

PCSK9

stimulates endocytosis of LDL receptors. more pcsk9 means fewer LDL receptors means more LDL floating around

targeting PCSK9

works in, like, everybody



conclusions from lipid therapy lecture

LDL-C strong risk factor for coronary artery disease



LDL-C can be lowered by statins, ezetimibe, pcsk9 antibodies, bile acid resins, niacin



TGs also appear to be a risk factor, though not as strong



can be lowered by fibrates, niacin, fish oil

PR interval normal, but HR < 60 bpm


QRS normal


QTc normal



Sinus bradycardia

brief irregular tachycardia followed by slower beats



bradycardia-tachycardia syndrome

no p waves evident


normal width qrs


HR < 50


junctional escape rhythm

no p waves evident


widenedQRS with a bundle branch block pattern


HR < 40



ventricular escape rhythm

PR interval: 260ms prolonged


QRS normal


QTc normal


prolonged PR and everything else okay = 1st degree AV block

start with short PR interval


PR interval lengthening


until eventually there's a P not followed by a QRS



2nd degree Type I


Mobitz type I


wenkebach block

regular PR interval


missing QRS


back to normal



2nd degree AV block


Mobitz Type II

Multiple QRS missing in a row



high grade 2nd degree type II AV block

P and QRS are unrelated


QRS looks like L or R BBB



3rd degree AV block

P waves and QRS complexes are normal but HR > 100



Sinus tachycardia

P wave occurs earlier than expected and its shape is abnormal



Atrial Premature Beat

rapid sawtooth atrial activity



atrial flutter

chaotic atrial activity without organized p waves


irregular qrs rate



atrial fibrillation

retrograde p waves occur with QRS



Paroxysmal Supreventricular Tachycardia (PSVT) caused by AV nodal re entry

shortened PR interval


delta wave in the QRS



Wolf Parkinson White syndrome


AKA


Ventricular Pre Excitation Syndrome

delta wave is fusion of ventricular activation via the av node and an accessory pathway



sinus rhythm

APB triggers orthodromic atrioventricular re entrant tachycardia



no delta wave



signals goes backwards up the accessory path and back down through the av node in this loop

QRS widened because ventricles are stimulated by abnormal conduction through the accessory pathway (it's slower?)



the signal runs backwards and up through the av nodal pathway and comes back down through the accessory pathway

arrows are on ventricular premature beats VPBs

monomorphic VT

widening QRS complexes with a waxing and waning pattern



torsades de pointes

V fibrillation

Myocardial oxygen supply comes from

O2 content



coronary blood flow:


coronary perfusion pressure


coronary vascular resistance



external compression


intrinsic regulation


local metabolites


endothelial factors


neural innervation



other answer:


blood flow


origin carrying capacity


O2 saturation

myocardial oxygen demand comes from

wall stress


(PxR)/(2h)



heart rate



contractility

oxygen supply

myocardial extraction of oxygen is near max at rest (about 75%)



increased supply must result from increased coronary flow - vasodilation and increased cardiac output



hemoglobin saturation with oxygen and hemoglobin level are vital to delivery of oxygen

oxygen supply: optimal flow


external pressure

greatest during systole



subendocardium is most vulnerable as it is adjacent to high intraventricular pressure


oxygen supply: optimal flow


internal factors

metabolic


during ischemia - cant produce atp


ADP and AMP are converted to adenosine



adenosine is a potent vasodilator and is the prime mediator of vascular tone -> decreased calcium entry into cells -> relaxation/vasodilation



endothelial growth factors like nitric oxide lead to vasodilation via cGMP mechanism



increased shear stress, ACh, thrombin, platelets - NO is released to compensate and lead to vasodilation

the most potent endogenous vasodilator?

NO

other endogenous vasodilators?

adenosine


NorEpi


TXA2

myocardial demand comes from

wall stress


Pr/2h



heart rate



contractility

why are beta blockers so useful in ischemia

longer time in diastole (increased flow)



lower wall stress (lower demand)



lower heart rate (lower demand)



lower contractility (lower demand)

consequences of an epicardial coronary stenosis

if stenoses < 70%, there is little change in blood flow at rest


with exercise, the artery is able to dilate to increase flow



if stenoses70-90%, there is autodilation of the resistance vessels at rest and the flow is normal


with exercise, cannot dilate further to meet the demand and there is ischemia



if the stenosis is >90%, there is maximal dilation of the resistance vessels at rest to the extent possible


flow at rest may be suboptimal

coronary pressure falls


subendocardial flow vs subepicardial flow

the subendocardial flow decreases prior to subepicardial flow

consequences of ischemia


the cascade

aerobic (fatty acid metabolism) is replaced byu anaerobic (glucose metabolism)



impaired diastolic function (it takes energy to relax!)



impaired systolic function



increased LV end diastolic pressure



increased lactate, serotonin, and adenosine



local metabolites and abnormalities in ion transport lead to ECG changes and arrhythmias



activation of peripheral pain receptors from C7 to T4

different effects of hypoxia


pulmonary vs coronary

lungs:


hypoxic vasoconstriction (don't want to perfuse a region of lung that isn't carrying oxygen)



coronary:


hypoxic vasodilation

when the wall motion appears abnormal, the muscle must be...

infarcted, stunned, or hibernating

myocardial infarct

no flow and no metabolically active cells

stunning

acute ischemia



time of abnormalities in movement and metabolism are related to time of ischemia




perfusion is normal following ischemia



occurs following coronary bypass surgery



function returns to normal within 1 week

hibernating

chronic ischemia



can result from frequent or prolonged ischemia



perfusion is usually reduced



down regulation of ATP uptake and oxygen consumption

viable myocardium

ability to improve motion or metabolism if coronary flow is improved

ischemic conditioning



pre conditioning

when the LAD artery of a dog is clamped repetitively for 5 minute intervals prior to prolonged occlusion, the area of infarction is less than if it is clamped without prior occlusion

ischemic conditioning



post conditioning

opening balloon in infarct-related artery to transiently occluded flow after opening the occlusion



upregulation of inducible NO synthase among other proposed mecehanisms

ischemic cascade

metabolic alteration



perfusion abnormalities



diastolic dysfunction



regional wall motion changes



ECG changes



angina

spectrum of coronary artery disease

noninvasive tests normal:


normal



fatty streak



plaque



increasing plaque



noninvasive tests abnormal:


obstructive atherosclerotic plaque



plaque fissure results in thrombosis

anginal syndromes



normal

patent lumen



normal endothelial function



platelet aggregation inhibited

anginal syndromes



stable angina

lumen narrowed by plaque



inappropriate vasoconstriction

anginal syndromes



unstable angina

biomarker negative


plaque rupture


platelet aggregation


thrombus formation


unopposed vasoconstriction

anginal syndromes



MI

biomarker positive



plaque rupture


platelet aggregation


thrombus formation


unopposed vasoconstriction

anginal syndromes



variant angina

no overt plaques



intense vasospasm


the spasms can slow flow

tests to assess presence of atherosclerosis



carotid IMT

no radiation


no contrast



thicker intimal lining = worse survival

tests to assess presence of atherosclerosis



coronary calcium scan

minimal radiation


no contrast



more calcium = less survival

tests to assess for atherosclersis



what about the stress test?

stress tests are for obstructive plaques >70%



below 70% you wont see anything on a stress test



if you don't have symptoms, a stress test won't tell you anything



most heart attacks are NOT caused by obstructive plaques, they're caused by non-obstructive plaques that rupture

likelihood of acute coronary syndrome



history

high likelihood:


chest or left arm discomfort as typical symptoms


worse with exertion or mental stress


alleviated by nitro


known CAD



intermediate:


new chest or left arm discomfort


>70 years old


male


diabetes mellitus



low:


recent cocaine use


probable angina (in absence of typical symptoms)

likelihood of acute coronary syndrome



exam

high:


mitral regurg


hypotension


diaphoresis


pulmonary edema



intermediate:


extracardiac vascular disease


(bruits or PAD)



low:


chest discomfort reproduced by palpation

likelihood of coronary syndrome



ECG

high:


new ST segment changes


T wave inversions with symptoms



intermediate:fixed q waves


abnormal ST/T waves or unclear duration



low:


T wave flattening


normal EKG

likelihood of acute coronary syndrome



cardiac biomarkers

high:


elevated troponin T

atypical angina symptoms

dyspnea


fatigue


arm discomfort


nausea


diphoresis



in women, elderly, diabetics

syndrome X

chest pain and abnormal stress test with normal epicardial coronary arteries



more common in women



more favorable prognosis than with coronary obstruction



may represent endothelial dysfunction or microvascular disease


can perform brachial reactivity test to assess for endothelial dysfunction



may treat with nitrates, ca channel blockers, ace inhibitors, beta blockers, statins

unstable angina features

symptoms at rest


increasing frequency


increasing duration


lower threshold for symptoms


biomarker negative (Troponin)



patients with unstable angina (troponin neg) or NSTEMI/STEMI (troponin pos) SHOULD NOT UNDERGO STRESS TESTING ON PRESENTATION

why do we perform cardiac stress tests>

to provide an exercise prescription



to identify the etiology of a patient's symptoms (Chest discomfort or dyspnea)



to risk stratify patients with known coronary artery disease



to assess for arrhythmias with exercise

when NOT to perform a stress test?

acute MI



high risk unstable angina



decompensated heart failure



uncontrolled cardia arrhythmias



AV block



acute myocarditis or pericarditis



severe aortic stenosis



severe HOCM



uncontrolled HTN



acute systemic illness - PE, Aortic dissection

major categories of stress testing:

one from each group!


group 1:


treadmill or bike/arm ergometry


adenosine or adenosine analogue


dobutamine (beta 1 agonist)



group 2:ECG


nuclear echo


cardiac MRI


PET

ischemic cascade AGAIN

metabolic alteration


perfusion abnormalities


diastolic dysfunction


regional wall motion changes


ECG changes


Angina

mechanism of imaging and the step in ischemic cascade it sees

PET - earliest (glucose metabolism -remember the heart switches to this during ischemia)



cardiac MRI - early (perfusion)



echocardiogram - late (systolic dysfunction)



ECG - latest

MET

metabolic equiv



unit of oxygen uptake in a resting state



1 MET is 3.5 ml O2/kg/min



more intense activities = more METs

maximal stress test

85% of maximum predicted heart rate



maximal predicted heart rate = 220-age

ECG evidence of ischemia

ST starts to drop (V4)



J point - compare 80ms after J-point to TP interval (to see baseline?)

non walker

if a patient cannot exercise, one can perform pharmacologic stress test (adenosine, persantine, or dobutamine)

pharmacologic stress testing - adenosine

at rest the distal arteries autodilate in the artery with the epicardial stenosis



during stress (with adenosine), the distal arterioles are already dilated so only the arterioles distal to the normal epicardial artery can dilate



at rest the flow to both septal and lateral myocardial is normal because the lateral coronary arterioles autodilate


with adenosine stress, the relative flow is increased more to the septal wall because the lateral wall arterioles are already maximally vasodilated

sensitivity of a test

likelihood to miss a positive (or correctly call someone as negative)

specificity of a test

likelihood to wrongly label someone as positive

rank of tests, most sensitive/specific to least

adenosine PET



exercise nuclear



exercise echo



exercise ECG

flowing blood to fibrin clot



how does it happen?

a complex "cascade" of events converts flowing fluid blood to a solid fibrin clot

vessel injury...

vasoconstriction (reduce blood flow)



coagulation cascade (thrombin -> fibrin -> stable hemostatic plug)



collagen exposure -> platelet activation -> platelet aggregation -> primary hemostatic plug -> stable hemostatic plug


vasoconstriction

slows the flow of blood and helps to limit blood loss



mediated by:


local controls (thrombaxane vasoconstricts)


systemic control (epi by adrenal glands stimulates)

the coagulation cascade bullet points

blood has more than a dozen clotting factors



coagulation involves a biological amplification system



sequential activation of a series of proenzymes or inactive precurosr proteins to active enzymes, resulting in significant amplification



culminates in the generation of thrombin



thrombin converts soluble plasma fibrinogen into fibrin



fibrin converts the unstable primary platelet plug to a more stable, firm hemostatic plug

pathwayway from vessel injury


coagulation cascade

VIIa converts tissue factor to TF VIIa



TF VIIa, VIIIA IXa, and V convert X to Xa Va



Xa Va convert prothrombin to thrombin



thrombin turns fibrinogen to a fibrin monomer



fibrin monomers polymerize



fibrin polymers are modified by XIIIa to be stable fibrin

control of the clotting cascade


extrinsic pathway

damage to tissue outside the vessel



tissue thromboplastin


inactive factor x to active factor x



active factor x turns prothrombin to thrombin



thrombin turns fibrinogen to fibrin



XIII turns fibrin to blood clot

control of the clotting cascade



intrinsic pathway

damage to the blood vessel



cascade of clotting factors turns inactive factor X to activated factor X



activated factor X turns prothrombin to thrombin



thrombin turns fibrinogen to fibrin



factor XIII turns fibrin to blood clotq

target sites in the coagulation cascade

TF



Xa Va



prothrombin



thrombin



fibrinogen



the stable fibrin

initiation of the clotting cascade

coagulation is initiated by the interaction of membrane bound TF exposed by vascular injury with plasma factor VIIa



TF-VIIa activates factor IX and factor X



Factor Xa without its cofactor forms small amounts of thrombin and prothrombin



^insufficient to initiate significant fibrin polymerization


activates several coenzymes: factor V, factor VIII, platelets, and factor VI



the initiation pathway is rapidly inactivated by TFPI (tissue factor pathway inhibitor)

after TFPI inactivates initiation pathway

thrombin generation is now dependent on the traditional intrinsic pathway which has been primed by the small amount of thrombin generated during initiation

amplification of the clotting cascade

thrombin generation is now dependent on the traditional intrinsic pathway -> primed by thrombin generated during initiation



in the amplification phase, intrinsice Xase activates sufficient Xa



Xa in combination with Va, PL, and Ca2+ leads to explosive generation of thrombin which acts on fibrinogen to form the fibrin clot

intrinsic Xase


VIIIa-IXa complex

greatly amplifies Xa production from X

prothrombinase complex

Xa, Va, PL, and Ca2+ leads to explosive generation of thrombin from prothrombin

thrombin activates

XI, V, XIII



thrombin also cleaves VIII from its carrier so that it cant help[ turn X into Xa-Va

thrombin activation of XIII

turns XIII into XIIIa and XIIIa turns fibrin polymer into stable fibrin

formation and stabilization of fibrin

thrombin hydrolyzes fibrinogen forming fibrin monomers



calcium acts like a glue to hold the fibrin monomers together to form a loose insoluble fibrin polymer



factor XIII is also activated by thrombin



activated factor XIII stabilizes the fibrin polymers



the stabilized meshwork of fibrin fibers traps erythrocytes, thus forming a clot that stops the flow of blood

coagulation and vitamin k

activity of factors II, VII, IX, and X - as well as protein C and S - is dependent upon vitamin K



vitamin k carboxylates a number of terminal glutamic acid residues on each of these molecules



vitam k comes from green vegetables and bacterial synthesis in the gut



vitamin k deficiency is caused by por diet, sever liver disease, malabsorption, or inhibition by VKA (warfarin)

physiological limitations of blood coagulation

unchecked blood coagulation would lead to dangerous occlusion of blood vessels if protective mechanisms were not in place



coagulation factor inhibitors


blood flow


fibrinolysis

coagulation factor inhibitors

effect of thrombin has to be limited to the site of injury



TFPI is synthesized in endothelial cells and present in plasma and platelets. it inhibits Xa and VIIa and TF



antithrombin is a circulating plasma portease inhibitor neutralizing many enzymes in the clotting cascade (especially thrombin and factor Xa)



heparin potentiates antithrombins action markedly


heparin is used int he treatment and prevention of clotting disorders

Protein C and Protein S

inhibitors of coagulation cofactors V and VIII (inactivating prothrombinase and intrinsic Xase



Vitamn K dependent proteins



as clot formation progresses, thrombin binds to thrombomodulin causing a confomrational change in thrombin that activates protein C



then protein C destroys factors VA and VIIIa, preventing further thrombin generation



activation of protein C is enhanced by protein S



activated protein C also enhances fibrinolysis

fibrinolysis

a normal hemostatic response to vascular injury


fibrinolysis


plasminogen

is converted to plasmin by activators from th e vessel wall or from the tissues



the most important route follows the release of tissue plasminogen activator (tPA) from the endothelial cells



APC destroys plasma inhibitors of tPA, thus stimulating fibrinolysis

fibrinolysis


plasmin

pjlasmin is capable of digesting fibrinogen, fibrin, factors V and VIII and many other proteins



cleavage of peptide bonds in fibrin and fibrinogen produces a variety of split (degradation) products

fibrinolytics agents

recombinant tPA was synthesized using recombinant DNA technology



the bacterial agent streptokinase is produced by hemolytic streptococci - forms a complex with plasminogen - and converts plasminogen to plasmin



Urokinase is a tPA initially isolated from human urine

endothelial cells

ECs have an active role in the maintenance of vascular integrity



provoides the basement membrane that separates collagen, elastin, fibronectin from the circulating blood



loss or damage to the endothelium results in both hemorrhage and activation of the clotting casade



ECs also have a potent inhibitory influence on the hemostatic response through the synthesis of NO, prostacyclin (PGI2), and the endonucleotidase CD39



In contrast, endothelins can activate fibrinolysis via the release of tPA

things endothelial cells produce

Tissue Factor


initiates coagulation



prostacyclin and nitric oxide


vasodilation/inhibition of platelet aggregation



vWF


platelet collagen adhesion, complex with factor VIII



antithrombin/TFPI/Protein S, Binding protein C, Actation of protein C


inhibition of blood coagulation



tPA


fibrinolysis

general causes of thrombosis

increased level of procoagulants



decreased levels of anticoagulants



abnormal fibrinolysis

inherited causes of thrombosis



inreased levels of procoagulants

factor V Leiden


Activaed protein C resistance



Prothrombin mutation



hyper homocysteinemia



factor VIII, IX, XI, VII, VWF


inherited causes of thrombosis



decreased levels of anticoagulants

antithrombin



protein c



protein s



thrombomodulin



tfpi

inherited causes of thrombosis



abnormal fibrinolysis

plasminogen deficiency



decreased tPA



increased PAI1



elevated TAFI

platelets

produced in bome marry by fragmentation of the cytoplasm in megakaryocytes


thrombopoietin

a major regulator of platelet production, produced in the l/iver and kidneys


normal platelet life span

7 to 10 days

platelets create interface etween

hemostasis, innate immunity, and inflammation in atherosclerosis

GP IIb/IIIa

fibrinogen receptor



makes the platelets stick together

platelets at work

damage to the vascular endothelium results in recruitment of platelets which aggregate at the site, forming the primary hemostatic plug



through the processes of adhesion, aggregation, and secretion, platelets successfully coalesce to complete the formation of the primary hemostatic plug

platelets and inflammation

enhanced expression of cell adhesion molecules (p-selectin and e-selectin) in a systemic inflammatory environment



platelets then secrete cytokines, chemokines, growth factors, adhesion molecules, and coagulation factors



platelets bind to circulating leukocytes, dendritic cells, and progenitor cells producing coaggregates that support further leukocyte activation, adhesion, and transmigration

is increased platelet activity important?

platelet hyper-reactivity following ACS predicts 5 year outcomes



hyper reactivity = more patients dying or having cardiac events

anti platelet therapy good and bad news

good news - it decreases cardiovascular events



bad news - it increases the risk of major bleeding

thrombosis versus bleeding in platelet therapy?

platelet activation


heart attacks


strokes


blood clots



platelet inhibition


major bleeding


transfusion


reoperation

virchow's triad

endothelial injury


abnormal blood flow


hypercoagulability



all three together can cause thrombosis

etiology of acute MI

coronary atherosclerosis



coronary thrombosis



myocardial necrosis

plaque vulnerability factors

size of atheromatous core



thickness of fibrous cap



inflammation and repair of fibrous cap


(macrophage activation)

acute coronary syndromes

unstable angina



non STEMI



STEMI

acute MI pathologic phases

ischemic insult



necrosis



healing



scarring

infarct size depends on

distribution of coronary artery



point of total occlusion

chest pain in acute MI

retrosternal, left side of chest, ulnar side of left arm



pressure, squeezing, constricting


>20 minutes, persistent


shortness of breath, diaphoresis

MI triggers

no trigger (51.1%)



emotional upset (18.4%)



moderate physical activity (14.1%)



heavy physical activity (8.7%)



lack of sleep, overeating, other (7.7%)

when do the most MIs happen?

Early in the morning

acute anterior wall MI



wide QRS and elevated ST?

acute anterior wall MI

acute anterior wall MI



see ST elevations start in V1



see reciprocal ST depressions in I, II, III, aVF

acute inferior wall MI



ST elevations in II, III, aVF



ST reciprocal depressions in V1, V2, V3

can't really see ST elevationsin II, III, aVF



but you DO see the reciprocal ST depressions in V2 and V3



acute inferior wall MI

diagnostic criteria of abnormal Q waves

width of q wave > 0.04 sec (40 msec)



depth of Q wave >25% of R wave



width is more importantw

hat causes pathologic q waves?

necrosis

evolutionary EKG changes of acute MI

acute


ST elevation



Hours


ST elevation, decreased R wave, Q wave begins



Days 1-2


T wave inversion


Q wave deepens



Days later


ST normalizes


T wave inverted



Weeks later


ST and T normal


Q wave persists

cardiac markers



yellow is CK-MB



pink is Troponin



green is LDH (not used anymore)



you can see that the troponin level starts earliest and spikes the highest. it also lasts longer.



CK-MB starts a bit after troponin but has a steeper slope and peaks sooner.

myocardial damage


left ventricular dysfunction

decreased ejection fraction



elevated LV volume and pressure

myocardial damage



decreased ejection fraction

leads to decreased stroke volume and cardiac output



systemic hypoperfusion

myocardial damage



elevated LV volume and pressure

elevated left atrial and pulmonary capillary pressures



pulmonary congestion

MI complications



LV dysfunction

pump failure



heart failure - rales



pulmonary edema



cardiogenic shock

MI complications extent of LV dysfunction

depends on degree of necrosis

MI complications


myocardial healing

Ventricular septal defect



ventricular free wall rupture



aneurysm formation

MI complications


involvement of papillary muscle

mitral regurgitation

MI complications


involvement of conduction system

heart block


av node, bundle branch system


MI complications


ventricular arrhythmias

secondary ischemia and scarring

more MI complications

pericarditis



postinfarction ischemia

MI treatment

open the occluded coronary artery



salvage/preserve threatened myocardium



limit the size of the infarction

pathophysiology of STEMI

generally caused by a completely occlusive thrombus in a coronary artery



results from stabilization of platelet aggregates at sites of plaque rupture by fibrin mesh



treated pharmacologically via thrombolysis and platelet antagonists



cather treatments are balloons and stents

thrombolysis

plasminogen is activated to plasmin



plasmin attacks fibrin which makes up the thrombus and fibrinogen in the circulation



creates fibrin degradation products

streptokinase

plasminogen activator



streptokinase binds with plasminogen to make the plasminogen streptokinase activator complex wihich converts plasminogen to plasmin



plasmin converts fibrin or fibrinogen to fibrin degredation products



50% successful reperfusion

tissue plasminogen activator

produced by normal endothelia



tPA is a serine protease



it works best whhen already in contact with fibrin



it converts plasminogen to plasmin



plasmin converts fibrin and fibrinogen to fibrin degradation products



less fibrinogen depletion and better targeted at fibrin



75% successful reperfusion

tissue plasminogen activator



fibrin specificity

kringle domains allow tPA to recognize and bind to fibrin



higher affinity for fibrin-bound plasminogen than for free circulating plasminogen



dissolves clots better than streptokinase



has a half life of 5 minutes


given as a bolus plus a 90 min infusion

tPA mutant forms

TNKase


half life is 5 to 7 x that of tPA


can give in a single bolus


has even better fibrin specificity



retaplase (rPA)


half life is 2-3x tPA


given as a double bolus

complicationsof thrombolysis

intracranial hemorrhage


increased risk over 65 years old, low body weight, severe hypertension



contraindications are prior intracranial hemorrhage, active bleeding, recent trauma



reocclusion is another complication


give thrombin antagonists and platelet inhibitor with the drug

indications for thrombolysis or acute PTCA/Stent

chest pain consistent with acute mI



EKG changes


ST segment elevation > 1mm


new bundle branch block



time from onset of symptoms < 12 hours

principles of reperfusion



determinants of survival

rapidity of reperfusion



magnitude of restoration of flow



persistence of flow



major complications are bleeding and reinfarction

pharmacology for thrombolysis therapy of MI

platelet antagonist


aspirin


clopidogrel/prasugrel


IIb/IIIa inhibitor



thrombin inhibitor


bivalirudin, heparin



beta blocker



ACE inhibitor

ADP P2y12 receptor antagonists


thienopyridines

require metabolic actiavtion via CYP2C19 pathway

ADP P2Y12 receptor antagonists



thienopyridines



clopidogrel (plavix)

4-8 h for peak onset of action



maximum platelet inhibition of 40-50%



many nonresponders due to genetic polymorphisms

ADP P2Y12 receptor antagonists



thienopyridines



prasugrel (effient)

faster onset of action than clopidogrel, works within 15m



more platelet inhibition than clopidogrel, 80% at one hour



greater efficacy and increasing vleeding vs clopidogrel



useful for STEMI

ADP P2Y12 receptor antagonists



cyclopentyl-trazalo pyrimidine

do not require activation

ADP P2Y12 receptor antagonists



cycoplentyl-trazalo pyrmidine



ticagrelor (brilinta)

onset of action similar to prasugrrel



degree of platelet inhibition slightly greater than prasugrel



greater efficacy and increased bleeding vs clopidogrel



useful in STEMI

Pharmacologic therapy post MI


survival benefit as acute therapy and chronic therapy

beta blockers


ACE inhibitors


aspirin

pharmacologic therapy post MI


NO survival benefit as acute therapy or chronic therapy

nitrates



magnesium



calcium blockers

normal medications for MI

anti-ischemic:


beta blocker


nitrates


calcium channel blocker



general measures:


pain control (morphine)


supplemental O2 if needed



antithrombotic-antiplatelet


aspirin


clopidogrel


GP IIb/IIIa inhibitor



antithrombotic-anticoagulant (use one)


LMWH


unfractionated intravenous heparin


fondaparinux


bivalirudin



adjunctive:


statin


ACE inhibitor

single leading killer in the western world

coronary artery disease

angina pectoris

discomfort or pain in the chest



occurs when coronary blood flow is inadequate to supply the oxygen requirements of the heart

stable angina

no change in frequency, severity, duration, or precipitating factors in the previous 60 days



generally occurs with exertion and relieved by rest



good prognosis

pathyphysiology of stable angina

one or more severe narrowings in a large epicardial coronary artery



generally due to ahtersclerosis without superimposed thrombus

stable angina

severely narrowed l umen



thick fibrous cap



distant lipid core

left is stable angina



right is unstable angina or vulnerable

stable angina treatment goals

relieve discomfort with medications that improve oxygen supply and/or reduce oxygen demand of the heart



revascularization by angioplasty or bypass surgery indicated if medical therapy fails



risk stratificataion, prevent progression of disease

useful medications for stable angina

beta adrenergic receptor antagonists



calcium channel blockers



nitrates



aspirin



statins



ranolazine for resistant angina on meds

vasospastic angina

can occur at rest or on exertion



may be associated with atherosclerosis



treated with nitrates and calcium channel blockers



statins may treat underlying endothelial dysfunction + aspirin



DONT use beta blockers

unstable angina

angina increasing in frequency, intensity, or duration



angina at rest



transient ecg changes



high risk of myocardial infarction and death in the ensuing months



usually a ruptured plaque -> thrombus in the vessel, not 100% occluded

pathphysiology of unstable angina

ruptured atherosclerotic plaque



partially occluding thrombus in lumen of large epicardial coronary artery

coronary thrombosis

plaque ruptures or fissures at high mechanical stress points



fibrous cap may thin due to monocyte production of proteases, which may chemically digest the plaque cap

coronary thrombosis


fibrous cap rupture

underlying tissue is exposed, clotting mechanisms are activated



thrombus forms



thrombus may be non occlusive and eventually be incorporated into the atherosclerotic plaque.

coronary thrombosis


partially occlusive

leads to the acute coronary syndromes, unstable angina or nonSTEMI



unstable angina = no enzymes



with enzymes its non STEMI

coronary thrombosis


totally occlusive

leads to the most common presentation of acute MI



sever chest pain



ST segment elevations

unstable angina treatment goals

relieve discomfort with medications that improve oxygen supply and/or reduce oxygen demand of the heart



prevent myocardial infarction and death



aggressive revascularization

useful medications in unstable angina

beta adrenergic receptor antagonists



calcium channel blockers



nitrates



aspirin



heparin - unfractionated and low molecular weight



newer anti platelet agents - GPIIb/IIIa receptor antagonists and thienopyridines



Statins

all antianginal agents work by either...

increasing O2 supply or decreasing O2 demand

determinants of myocardial O2 supply

oxygen carrying capacity (hemoglobin)



coronary arteriolar resistance



duration of diastole (heart feeds in diastole)



intra-coronary pressure gradients


atherosclerosis


vasospasm

myocardial O2 demand

wall stress = (PxR)/(2h)



p = intraventricular pressure (vascular resistance)


r = ventricular radius (volume)


h = wall thickness



heart rate


contractility



surrogate for O2 demand is systolic PxHR

antianginal medications

first line:


nitrates


calcium channel blockers


beta blockers



second line:


ranolazine

nitrates: mechanism of action

venodilation and arteriodilation, but more venous



reduction in preload, decrease in blood return to the heart, heart size decreases



reduction in blood pressure and therefore in afterload



attentuation of coronary vasospasm



improved collateral blood flow

nitrate effects in angina

decreased myocardial oxygen requirement by decreasing wall stress both P and R



possible improved oxygen delivery



decrease P, decrease R, then you decrease O2 requirement

nitrates: cellular mechanisms

enzymatic degradation to nitric oxide



activation of intracellular guanylyl cycloase in smooth muscle by NO



increase cGMP



dephosphorylation of myosin light chain phosphate, inactivating myosin-actin interaction leading to vasodilation



effects only on smooth muscle, no effects on cardiac or skeletal muscle

nitrate mechanism

nitrates become ONO2



reduced to NO2



reduced to NO



NO turns on guanylyl cyclase



GTP+ guanalyl cyclase makes cGMP



cGMP causes vasodilation

nitrate mechanism contd

nitric oxide activates guanylyl cyclase



gtp converted to cGMP by guanylyl cyclase



myosin light chain has a phosphate on it that allows it to bind to actin causing vasoconstriction



when the phosphate is removed by cGMP, the myosin light chain can't bind actin and the vessel relaxes

phosphodiesterase



viagra?

phosphodiesterase breaks cGMP down to GMP



viagra (and any other phosphodiesterase inhibitor) will keep that from happening, meaning you have too much cGMP and too much relaxation

adverse effects of nitrates

headache


orthostatic hypotension


reflex tachycardia due to vasodilation



tolerance to nitrates can develop and they'll stop working



rebound due to nitrate withdrawal

possible mechanisms for tolerance to nitrates

sulfhydryl group depletion



salt and water retention



increased free radicals that degrade NO

nitrates have to get to circulation without

going to the liver first. thats why theyre put sublingual usually

calcium channel blockers


mechanism of action

arterial vasodilation more than venodilation


lowers blood pressure



potent coronary artery dilation


drugs of choice for coronary vasospasm



negative inotropy



negative chronotropy

calcium channel blockers


cellular mechanisms

blockade of voltage dependent L type calcium channels



the L type calcium channel is the dominant calcium channel



it has several receptors and the different classes of drugs bind to different receptors



reduction in transmembrane calcium flux



skeletal muscle isn't depressed by the calcium channel blockers because it uses intracellular pools of calcium to support excitation-contraction coupling and does not require much transmembrane calcium influx

blocking the calcium channel in diferent places...

on vascular smooth muscle it results in vasodilation



on the myocardium results in reduced inotropy



on the SA node and AV node it results in slowed conduction



on the GI tract it results in decreased peristalsis

calcium channel blocker effects in angina

increases O2 supply


relieves vasospasm


some prolong diastole



decreases O2 demand


decreased inotropy


vasodilation decreases arterial pressure (lowers wall stress)


some classes slow the heart rate

classes of calcium antagonists

first gen dihydropyridines



second gen dihydropyridines



phenylalkamines



modified benzothiazepines

calcium channel blocker


first gen dihydropyridine


nifedipine

potent vasodilator


greater effect on vascular smooth muscle than cardiac muscle



may cause reflex tachycardia so it should be used with a beta blocker



negative inotrope (usually not a problem because of increased CO due to vasodilation)



short acting preparation removed from market due to risk of MI and stroke secondary to hypotension



long acting preparations

nifedipine adverse effects

headaches



dizziness



lower extremity edema (diuretics dont work for this kind of edema)



flushing

verapamil

ca channel blocker



potent negative chronotrope



negative inotrope



systemic and coronary vasodilator



useful as an antiarrhythmic agent for supraventricular tachycardias

verapamil adverse effects

headache



flushing



lower extremity edeme



constipation (greater effect on peristalsis)



excessive sinus bradycardia and AV block



CHF exacerbation (because of decreased inotropy)



increases digoxin blood levels

diltiazem

ca channel blocker



less potent vasodilator than nifedipine



less potent negative chronotrope than verapamil



negative inotrope



iv form useful for controlling ventricular rate in a fib (slows the av node)

diltiazem adverse effects

headache



flushing



lower extremity edema



excessive sinus bradycardia and AV block



CHF exacerbation

Amlodipine

safest ca channel blocker in patients with CHF



well tolerated



once a day

beta receptor subtypes



beta 1

predominate in the heart



stimulation results in increased heart rate, av conduction, and contractility

beta receptor subtypes



beta 2

predominate in the lungs and liver



stimulation results in bronchodilation, vasodilation, and glycogenolysis

beta blocker mechanism of action

negative chronotrope, negative inotrope



lower blood pressure



increase duration of diastole



attenuate exercise mediated increases in contractility and heart rate



anti arrhythmic effect suppresses lethal ventricular arrhythmias



survival benefit in patients post MI and with compensated CHF

beta 1 selective beta blockers

atenolol



metoprolol

adverse beta blocker effects

bronchocnostriction



exacerbation of chf



impotence



depression



excessive sinus bradycardia and av block



masking of hypoglycemia in diabetics

ranolazine (ranexa)

first new class of antianginals in more than 20 years



indicated for patients who continue to have angina on standard antianginals or for those who cannot tolerate standard antianginals



works by blocking the late I(Na) channel



may be used in pts with low heart rate or low bp, CHF, DM, or asthma

origin of late I(Na)

during the plateau phase of the AP, a small proportion of Na channels either do not close, or close and then reopen



these late channel openings permit a sustained Na current to enter myocytes during systole

myocardial ischemia and late I(Na)

it causes enhnaced late I(Na)



enhanced late I(Na) appears to be a major contributor to increased intracellular Na during ischemia

role of altered ion currents in adverse consequences of myocardial ischemia

increase in late I(Na) causes too much sodium entry into the cell which causes too much Ca in the cell



too much calcium causes electrical instability and mechanical dysfunction



afterpotentials


APD


arrhythmias (VT)



abnormal contraction and relaxation


increased diastolic tension

sustained contractoin of ischemic tissue during diastole

increases myocardial oxygen consumption



compresses intramural small vessels



reduces myocardial blood flow



overall it exacerbates ischemia

ranolazine mechanism of actionin

creased intracellular calcium does not allow normal LV relaxation



leads to increased O2 consumption and potential compression of hte vascular supply



ranolazine blocks the late I(Na) channels and therefore prevents intracellular calcium overload



pts experience less chest pain and improved exercise duration

strategies in the medical treatment of stable angina


beta blockers are the first line



pts should be given a bottle of sublingual nitro and instructed on use



calcium channel blockers used if beta blockers are contraindicated or not tolerated


may be added if angina persists or to treat HTN



rannolazine for persistent angina



risk stratificatoin (high risk -> cath)



plus aspirin and a statin

strategies in the medical treatment of unstable angina

hospitalization



treatment of angina, usually with nitrates sublingual or IV


often give beta blockers oral or IV



treatment of underlying ruptured plaque with thrombus -


aspirin


plavix


statin


antithrombin like heparin


other antiplatelet agents



risk stratification with cardiac cath

definition of thrombosis

formation of intra-vascular blood clot

thrombosis clinical significance

acute coronary syndrome



embolic stroke



pulmonary embolism

underlying cause of thrombosis

abnormality of normal hemostatic mechanism

thrombosis vs hemostasis



thrombosis

intravascular blood clot




compromises blood vessel lumen and impedes blood flow


thrombosis vs hemostasis



hemostasis

extra vascular blood clot located on external surface of blood vessels



prevents bleeding after vascular injury

thrombosis pathophysiology

endothelial injury



platelet activation



coagulation cascade



stasis

endothelial injury...

exposes underlying collagen



releases tissue factor



impairs endothelial cell production and release of anti-thrombotic factors: NO, prostacyclin, tissue plasminogen activator, tissue factor pathway inhibitor

platelet activation

initiated by collagen



shape change and degranulation



platelet delivers drugs



recruit of circulating platelets by ADP



glycoprotein IIb/IIIa receptor stimulation is the final common pathway of platelet aggregation

things platelets deliver on their own

adenosine diphosphate



factor V



platelet factor 4



platelet derived growth factor



tgf beta



thromboxane A2



serotonin

Glycoprotein IIb/IIIa receptor stimulation on platelet

its normally inside the platelet



it sticks out when activated



they can attach to fibrinogen and attach to each other through the fibrinogen

coagulation cascade simplified schema

endothelial injury leads to TF release



TF activates factor VII



factor VIIa complex activates factor X



Factor Xa+Va (prothrombinase complex) makes thrombin IIa

modulation of thrombin activity



increased

Xa+Va leads to thrombin formation



thrombin converts V to Va to Thrombin generation (positive feedback loop)

modulation of thrombin activity



decreased

circulating proteins C and S inactivate Va, leads to reduced thrombin formation



circulating anti-thrombin III directly inactivates thrombin

drug classes used to prevent thrombosis

anti-platelet agents



anticoagulants

antiplatelet agents

salicylates



ADP receptor antagonists



cAMP agonists



Thrombin receptor antagonists



glycoprotein IIB/IIIa antagonists

salicylates (aspirin)

weak platelet antagonists



irreversible acetylation and inactivation of cyclo-oxygenase blocks TxA2 production



indicated for MI and secondary prevention of MI and stroke prevention in low risk a fib



main side effect is GI bleeding



doses of ASA as low as 75mg every other day impair platelet function

ADP receptor antagonists

ticlopidine


clopidogrel


prasugrel


ticagrelor


what adp receptor antagonists do

more potent than ASA



block the P2Y12 receptor to prevent recruitment of circu lating platelets



clinical effects are irreversible for days



thienopyridines are prodrugs metabolized by cytochrome p450 to the active compound



potential for drug drug interactions



CYP2C19 reduced function allele associated with reduced response to clopidogrel

clinical use of ADP antagonists

indicated for stroke prevention in patients with prior stroke or TIA



indicated for a year after acute coronary syndrome



2-4 week course post bare metal stent



prolonged course (possibly for life) after implantation of drug eluting stents

cAMP antagonists



dipyridamole

inhibits uptake of adenosine by platelts, endothelial cells, and erythrocytes increasing local adenosine levels leading to platelet adenylate cyclase activation



indicated for stroke prevention in patients with normal sinus rhythm



vasodilator may cause coronary steal

cAMP antagonists



cilostazol

inhibits phosphodiesterase type 3



indicated as a vasodilator in vascular disease



contraindicated in heart failure

thrombin receptor antagonists



vorapaxar

approved by fda in may 2014 for secondary prevention post MI



increased risk of intracranial hemorrhage in patients iwth prior stroke

glycoprotein IIB/IIIa receptor antagonists

most potent platelet antagonists available



only available in IV form



used for treatment of acute coronary syndromes



abciximab - chimeric human/mouse FAB fragment derived from a monoclonal antibody



tirofiban and eptifibatide - small molecule short acting specific blockers



main side effect = excessive bleeding

antiplatelet medications



aspirin

PO



indicated for ACS treatment and prevention, low risk stroke prevention in Afib

antiplatelet medications



ADP receptor antagonist

PO



acs, post stent

anti platelet medications



cAMP antagonist

PO



stroke prevention in NSR, vascular dis

anti platelet medicataions



PAR-1 antagonist


PO



secondary prevention Post-MI

anti platelet medications



GPIIBIII antagonist

IV



treatment of ACS

anticoagulants

warfarin



unfractionated heparin



low molecular weight heparins



Xa inhibitors



direct thrombin inhibitors

warfarin

oral anticoagulant indicated for chronic use



inhibits synthesis of vitamin K dependent clotting factors II, VII, IX, and X



inhibits synthesis of proteins C and S

indicationsfor warfarin therapy

mechanical heart valve prosthesis


afib (stroke)


pulmonary embolus (secondary prevention)


DVT (secondary prevention)


recent anterior wall myocardial infarction

disadvantages of warfarin

slow onset (2 days of treatment to get effect)



requires monitoring of blood work



interacts with drugs and foods



bleeding



hemorrhagic skin necrosis



teratogenic (birth defects)

warfarin reversal

oral vitamin K (may lead to prolonged resistance to warfarin)



IV vitamin K


low dose for temprary reversal


high dose for anaphylaxis



iv clotting factors

Noval Oral Anticoagulants


NOACs

approved by FDA for stroke prevention in setting of non valvular a fib and for prophylaxis and treatment of dvt



rapid onset of action


no monitoring needed


no interaction with food



safer than warfarin



NO REVERSAL AGENTS



more expensive

list of NOACs

dabigatran


direct thrombin inhibitor



rivaroxaban


xa inhibitor



apixaban


Xa inhibitor



edoxaban


Xa inhibitor

unfractionated heparin

mixture of sulfated mucopolysaccharides derived for porcine intestinal mucosa and bovine lung



binds to and activates antithrombin III



heparin-antithrombin III complex inhibits thrombin, inhibits Xa, and enhnaces activity of TFPI



can be reversed by protamine

indications for heparin therapy

anticoagulation during initiation of warfarin therapy



acute coronary syndromes



cardiac cath, cardiac surg, and vascular surge



SQ heparin indicated for prophylaxes of venous thrombo-embolic disease

disadvantages of heparin therapy

non specific binding of heparin to plasma proteinsresults in variable dose response



bleeding



osteoporosis



rebound hypercoagulable period



heparin induced thrombocytopenia

effect of saccharide chain length on anti Xa: anti IIa ratio`

12 sugars on ATIII lets thrombin bind



only the 5 sugars ATIII is bound to lets Xa bind to it

low molecular weight heparin

same mechanism as heparin



less protein binding, more reliable anticoagulant effect



subq administration



fewer side effects

Xa inhibitors

fondaparinux



rivaroxaban



edoxaban

Xa inhibitors



fondaparinux

synthetic penteasaccharide results in antithrombinIII mediated inhibition of XA



subq administration



indicated for prevention of dvt



may be used for therapy of acute coronary syndrome

Xa inhibitors



rivaroxaban

oral therapy approved nov 2011 for stroke prevention in patients with a fib

Xa inhibitors



edoxaban

oral therapy approved jan 2015 for stroke prevntion in patients with a fib

Direct thrombin inhibitors

hirudin



bivalirudin



lepirudin



agratroban



dabigatran

direct thrombin inhibitors



hirudin

active component of the leech salivary gland



no longer in clinical use

direct thrombin inhibitors



bivalirudin

specific and reversible thrombin inhibitor



used for anticoagulation during coronary intervention

direct thrombin inhibitors



lepirudin

IV therapy for heparin induced thrombocytopenia

direct thrombin inhibitors



argatroban

IV therapy for heparin induced thrombocytopenia

direct thrombin inhibitors



dabigatran

oral therapy for smoke prevention in pts with a fib

hirudin vs bivalirudin



hirudin

irreversible



recombinant DNA



65