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Flashcards in CV Week 1a Deck (179):
1

Function of cardiovascular system (4)

1) Distributes dissolved gases and nutrients

2) Removes metabolic waste

3) Contributes to systemic homeostasis by controlling temp, O2 supply, pH, ionic composition, nutrient supply

4) Quickly adapts to changes in conditions and metabolic demands

2

The heart is a _____ pump. Two sides work _________ but there is NO __________

dual

in parallel

direct connection between them

3

Left side of the heart (4)

1) pump blood to systemic circulation

2) High pressure

3) Multiple pathways from heart to different vascular beds

4) Arranged in PARALLEL

4

Parallel arrangement of systemic circulation is useful for 3 reasons

1) Oxygenated blood visits only one organ system before returning to pulmonary circulation

2) Changes in metabolic demand or blood flow in one organ do not significantly affect other organs

3) Blood flow to different organs can be individually varied to match demand

5

Right side of the heart (3)

1) pump blood to pulmonary circulation

2) Low pressure

3) Single pathway through single set of capillary beds between heart/lungs

6

The right and left side of the heart are arranged in ________

series

7

Layers of the hear from inside to outside (4)

1) Endocardium
2) Myocardium
3) Epicardium
4) Pericardium containing pericardial fluid

8

Heart valves

-two sets, all valves located on same horizontal plane of heart.

-Valves are one-way and pressure-operated = PASSIVE

-Thin flaps of fibrous tissue covered by endothelium

-Heart sounds generated by opening and closing of valves

9

Atrioventricular valves

Tricuspid and mitral

-between atria and ventricles

-Attached to papillary muscles inside ventricles by chordae tendonae
(Prevents prolapse of valves)

10

Tricuspid valve

between right atrium and the right ventricle

11

Mitral valve

between left atrium and left ventricle

BICUSPID

12

Semilunar valves

Aortic and pulmonic valves

-Between ventricles and great arteries

-NO chordae tendons

13

Pulmonic valve

between right ventricle and pulmonary artery, tricuspid

14

Aortic valve

between left ventricle and aorta, tricuspid

15

Working myocytes vs. Nodal myocytes

Working myocytes (atrial and ventricular myocardium) = large

Nodal Myocytes (SA and AV node) = smaller, specialized for electrical conduction instead of contraction

16

Deoxygenated blood flow through heart (4)

1) Deoxygenated blood returns from systemic circulation via superior and inferior vena cavae, passively enters RA (no valve)

2) RA contracts → increased pressure pushes open tricuspid valve

3) Blood enters RV → RV contracts → pushes open pulmonic valve

4) Blood enters pulmonary circulation via pulmonary arteries

17

Oxygenated blood flow through heart (4)

1) Oxygenated blood returning from the lungs enters LA via pulmonary vein

2) LA contracts → pushes open mitral valve → blood enters LV

3) LV contracts → pushes open aortic valve

4) Blood enters systemic circulation via aorta

18

Aorta

single outlet from heart; d=2.5 cm.

Elastic and smooth muscle fibers in walls dampen pulsatile flow

19

Arteries

thick walled, resist expansion, d=0.4 cm

Distribute blood to different organs

20

Arterioles

relatively thick walls (lots of vascular smooth muscle); d = 30 um.

Highly innervated → primary site of regulation of vascular resistance.

21

3 layers of arterioles and their importance

1) Tunica intima = inner layer
-Connective tissue and vascular endothelium
-Important for signaling
-Site of atherosclerotic plaque formation

2) Tunica media = middle layer
-Innervated smooth muscle cells, control vessel diameter

3) Tunica adventitia = outermost layer
-Connective tissue (collagen + elastin)

22

Capillaries

smallest vessels

Walls are single layer of epithelium (approx same size as RBCs), d = 6 um

Exchange vessels

23

Venules/Veins

-thin walls relative to similar diameter arteries - d = 20um-0.5cm

-“Capacitance vessels” - hold most of blood volume
Still some smooth muscle, not much elasticity

-Low pressure

-One way valves

24

Vena cava (inferior and superior)

two branches that input to heart; d=3 cm

Large diameter, but very thin wall

Very low pressure

25

Microcirculation

-vasculature from first-order arterioles to venules.
Responsible for exchange and filtration

-Capillaries = site of gas, nutrient, and waste exchange

-Highly regulated via constriction/dilation of arterioles and precapillary sphincters

-Movement of substances between capillaries and tissue is driven by concentration and pressure gradients

26

Function of lymphatic system

-pathway for fluid and large molecules to move from interstitial space to blood

-Lymph flow within lymphatic capillaries is driven by contraction of smooth muscle in lymph vessels, and contraction of surrounding skeletal muscle

-One way valves - unidirectional flow

27

Flow equation

Q = ΔP/R

Q = flow (ml/min)
ΔP = pressure difference
R = resistance

28

Key rules to remember about flow (3)

1) **Total flow is CONSTANT through system

2) Total flow through system = CARDIAC OUTPUT (CO)

3) **Flow in MUST equal flow out

29

↓ vascular resistance = _____ flow

↓ vascular resistance = ↑ flow

30

Resistance in parallel ______ total resistance

DECREASES

-Resistance of parallel network LOWER than resistance of any single vessel
-Changing resistance of single vessel has little effect on system

EX) total resistance of cap beds is low and INDEPENDENT of individual capillaries (because there are many parallel vessels)

31

Resistance in series are ________

ADDITIVE

-Total resistance of a series of vessels is higher than resistance of any individual vessel

-Arteriole resistance is the MOST significant for total resistance

32

Poiseuille's Law

Q=(ΔP) x (π r^4) / 8hl (know effect of variables, not specific equation)

r = radius
h = viscosity of blood
l = length

33

Radius effect on flow

**Radius of vessel has HUGE effect (to 4th power) on flow

34

increase viscosity = ______ flow

DECREASE

35

Increase length = ______ flow

DECREASE

36

Pulsatile flow

heart pumps intermittently, creating a pulsatile flow in aorta

Pulsatile flow requires more work

Analogy: stop and go driving requires more gas

37

Systolic vs. Diastolic

Systole vs. Diasatole

Systolic = peak aortic pressure
Diastolic = minimum aortic pressure

Systole = contraction
Diastole = relaxation

38

Steady flow

once blood reaches the capillary beds, there is no pulse variation, pressure (and thus flow) is constant and continuous.

Conversion of pulsatile → steady flow achieved via compliance in main arteries.

39

Mean arterial pressure (MAP)

Diastolic pressure + (⅓) x (systolic pressure - diastolic pressure)

40

Vascular compliance equation

C=ΔV/ΔP

(change in volume/change in pressure)

41

Vascular compliance

-Represents elastic properties of vessels (or chambers of the heart)

-Proportion of elastin fibers vs smooth muscle/collagen in vessel walls

-Degree of compliance in main arteries contributes to transformation of pulsatile flow in microcirculation.

-More compliance in aorta = lower pulse pressure

42

Ateriosclerosis

loss of compliance caused by thickening and hardening of arteries

*Some arteriosclerosis is normal with age

NOT the same as atherosclerosis

43

LaPlace's Law equation

LaPlace’s Law: T = (ΔPtm)(r) / u

T = tension/wall stress
ΔPtm = transmural pressure (pressure across the wall)
r = radius
u = wall thickness

44

Decreased wall thickness = ______ tension

increased

45

Aneurysm

weakened vessel wall bulges outward

↑ radius = ↑ tension that cells in vessel wall must withstand to prevent vessel from splitting open

-Over time, cells become weaker → wall bulges more → ↑ tension further, until aneurysm ruptures

46

Fick's Principle equation

Xtc = [Xi] – [Xo]


-Xtc = Amount of substance X used in capillary (transcapillary efflux)

-Xi = amount of substance X that went into the capillary

-Xo = amount of substance X that came out of the capillary

47

Hydrostatic pressure promotes _________

FILTRATION (movement of fluid out of capillaries)

48

Oncotic pressure promotes ________

REABSORPTION (movement of fluid into capillaries)

49

Hydrostatic pressure (P)

fluid pressure

Net hydrostatic P in capillary bed = capillary pressure - interstitial pressure

Solvents move from high pressure to low pressure.

50

Oncotic pressure (p)

0osmotic force created by proteins in blood and interstitial fluid

-Alpha-globulin and albumin are major determinants of oncotic pressure.

-Solutes move from high concentration to low concentration

-Solvents move toward high concentrations of solutes.

51

Starling's Equation for transcapillary transport equation

Flux = k [ ( Pc – Pi ) – ( pc – pI ) ]

Pc – Pi: net hydrostatic pressure; tends to be outwards (filtration)

pc – pI: net oncotic pressure; tends to be inwards (reabsorption)

52

You can get excess filtration due to _____ or ________.

Excess filtration causes ________

Increased BP (HTN) or reduced oncotic pressure (liver disease)

EDEMA in tissues

53

Net flux is ______ from arterial to venous end of capillaries

Pc is _____ on arterial side and ______ on venous side

pc is _______ on arterial side and ______ on venous side

NET RESULT?

NOT CONSTANT

Pc = high, low
pc = low, high

Net result = tendency for filtration on arterial side, reabsorption on venous side

54

Net flux is primarily controlled by ________

control of capillary hydrostatic pressure

Vasoconstriction / vasodilation of arterioles

Net flux is different in different capillary beds

55

Special Features of Cardiac Muscle (7)

1) Autonomic

2) Composed of interconnected mononucleated cells embedded in collagen weave (Type I and III)

3) Much longer repolarization than skeletal muscle (prevents tetanus)

4) ATPase activity is slower than skeletal muscle

5) **Thin filament (troponin) regulation of contraction

6) Coupling between cells is both mechanical and electrical

7) Rich in mitochondria, large number of myofibrils (85% myofibrils/mitoch)

56

Electrical and Mechanical coupling of cardiac myocytes accomplished by...

Desmosomes = adhesion, force generated in one cell passes to the other → mechanical coupling

Gap junctions = resistance pathways for current → electrical coupling

57

Myosin

two heavy chains and four light chains = thick filament

58

Actin

similar to skeletal muscle actin; binds tropomyosin and troponin.

Thin filaments - length does NOT change, slides across mysoin

59

Titin

massive protein that functions as a molecular spring connecting Z line and M line of the sarcomere

Two isoforms - N2B (more stiff) and N2BA

Cardiac titin isoform is very stiff (low compliance, decreased preload)

60

TN-C

Thin filament regulatory protein (troponin)

calcium binding, contains only one Ca2+- binding site.

61

TN-I

Thin filament regulatory protein (troponin)

-inhibitory, interacts with TN-C, but released with phosphorylation

-Contains unique N-terminal extension of 32 amino acids which is highly regulated by Phosphorylation

62

TN-T

Thin filament regulatory protein (troponin)

-binds tropomyosin, regulates calcium-sensitivity

-Isoforms are developmentally and pathologically regulated.

63

Tropomyosin (TM)

overlays actin blocking myosin binding site

only alpha isoform in cardiac muscle cells (skeletal muscle has alpha and beta)

64

cardiac muscle cell at rest

low intracellular Ca2+, TN-™ complex inhibits actin-myosin combination

65

Cardiac muscle cell contraction (5 steps)

1) AP → Increase in myoplasmic Ca2+

2) → Ca2+ binds TN-C

3) → TN-I releases inhibition, TM moved out of actin groove

4) → myosin binds actin and crossbridge moves (myosin head undergoes power-stroke)

5) → myofilaments shorten

66

Cardiac muscle cell relaxation

Calcium released, TM re-blocks binding site → relaxation

67

4 state cross-bridge cycle

1) Relaxation (Diastole): no Ca2+, myosin weakly bound to actin

2) Transition State: Ca2+ bound, cross-bridge not force generating

3) Active State: Ca2+ bound, cross-bridge force generating

4) Active State: No Ca2+ bound, crossbridge strongly bound, force generating

68

Length-tension relationship is responsible for the regulation of _______

pre-load

69

Length tension relationship and preload

When cardiac muscle is stimulated to contract at low resting lengths (low preload), amount of active tension developed is small.

Increase muscle length (increased preload) → active tension developed dramatically increases

70

3 Molecular bases of Length-Tension relationship

1) Increased Ca2+ sensitivity of myofilaments increases as sarcomeres are stretched

2) Increased calcium release

3) Extent of overlap

71

Increased Ca2+ sensitivity of myofilaments increases as sarcomeres are stretched?

Regulated by what two proteins?

Same amount of calcium → greater force of contraction

Regulated by:

1) TN-T N-terminal extension decreases Ca2+ sensitivity

2) PKA phosphorylation of TN-I decreases Ca2+ sensitivity

72

Frank-Starling Law

Increased in preload leads to an increase in stroke volume

73

Factors that effect stroke volume (3)

1) Preload
2) Afterload
3) Contractility of myofilament

74

Preload

initial length of myocyte, sets length-tension relationship

75

Increased ventricular volume --> ?

1) increase ventricular circumference → increase length of each cardiac muscle cell

2) greater force required from each muscle cell to produce given intraventricular pressure

76

Increased tension of cells in heart wall --> ?

increased intraventricular pressure

77

Afterload

pressure ventricle must generate to eject blood out of chamber (approximately equal to aortic pressure)

Increase systemic pressure → heart works harder to overcome

Increase afterload = decrease velocity

Thick filament mediated

78

Contractility of myofilament is primarily determined by __________

calcium sensitivity

79

Cardiac output (CO) = ?

stroke volume x heart rate

Volume of blood pumped per minute by LV

80

CO at rest

4-6 L/min

* can be increased by up to eight fold during strenuous exercise

81

Stroke volume (SV)

volume of blood pumped per beat

82

SV is determined by (3)


1) Strength of contraction (Inotropy)
a.Length dependent intrinsic regulation (Starling’s Law)
b.Length independent regulation via sympathetic nervous system

2) Preload (venous return)

3) Afterload (resistance to flow, aortic pressure)

83

4 phases of cardiac cycle

1. Filling phase
2. Isovolumetric contraction phase
3. Ejection phase
3. Isovolumetric relaxation phase

84

Filling phase

end of diastole, LA filled with blood from pulmonary vein

1.Contraction triggered by electrical signal that originates at SA node

2.As atrium begins to contract, atrial pressure increases.
- ↑ atrial pressure
- .no change in volume

3.“The A wave” in both atrial pressure and ventricular pressure = atrial systole
- Mitral valve OPEN → blood flows freely into ventricle as atrium contracts

85

Isovolumetric contraction phase

1. Wave of depolarization reaches ventricle → begins to contract, ↑ ventricular pressure

2.Initial increase in pressure pushes mitral valve closed
- Ventricular pressure quickly exceeds that in the atrium.

3.BUT aortic pressure initially greater than ventricular pressure, so aortic valve also closed during initial stage of ventricular contraction → ventricular pressure increases rapidly because ventricle is contracting but the blood has no place to go

- No change in volume

86

Ejection phase

ventricle continues to contract, ventricular pressure exceeds that in the aorta → aortic valve pushed open, blood begins to flow

1.↓ ventricular volume

2. ↑ and then ↓ in ventricular pressure.

87

Isovolumetric relaxation phase

ventricle begins to relax, ↓ventricular pressure

1.Ventricular pressure drops below aortic pressure → aortic valve closes
- Ventricle continues to relax with both valves closed → pressure falls rapidly.

2.Ventricular pressure ↓ slowly at first and then rapidly.

3.Ventricle continues to relax, pressure eventually falls below that in atrium → mitral valve opens, blood flow into ventricle begins new cycle

88

Summary of volume changes in cardiac cycle (3)

1) Ventricle passively fills, with slight hump toward end of diastole when atrium contracts

2) Then, during isovolumetric contraction phase, there is no change in volume, because aortic and mitral valves are closed.

3) When aortic valve opens, blood can leave ventricle, and volume decreases

89

Summary of pressure changes in cardiac cycle (3)

1. After diastole and passive filling of LA with blood, contraction of atrium results in increased atrial pressure, followed by an increase in ventricular pressure (while the mitral valve is open)

2. Once mitral valve is closed and ventricular contraction commences, ventricular pressure increases rapidly until ventricular pressure exceeds that in aorta and aortic valve is pushed open.

3. This immediately results in a slow decrease in ventricular pressure followed by a much faster drop in ventricular pressure once ventricular pressure drops below aortic pressure and aortic valve. Ventricle continues to relax with both valves closed, so pressure falls rapidly.

90

Pressure and volume changes in the left ventricle are bounded by two curves:

Systolic and End Diastolic Pressure-Volume Relation

91

End-diastolic pressure volume relationship (EDPVR):

pressure-volume relationship during filling of heart BEFORE contraction

i.Passive elastic properties of ventricle (compliance)

92

High compliance = ____ slope of EDPVR

Shallow

1. Not much change in pressure with an increase in volume

2.Some pathologies ↓ compliance, making EDPVR steeper, impairing ventricle.

93

EDVPR represents ____ on left ventricl

preload

94

Systolic pressure volume relationship (SPVR):

pressure-volume relationship at peak of isometric contraction

i. Much steeper than EDPVR—pressure increases even at low volume.

ii. SPVR includes active and passive properties of the heart.

95

Active tension

difference in force between peak systolic pressure and end diastolic pressure (tension developed by contraction)

96

Frank-Starling Law of the Heart (4)

i. INTRINSIC property of heart
- Independent of ANS regulation
- Dependent on sarcomere length-tension relationship
- Adapts to changes in preload (in normal physiologic range)

ii.Heart response to an ↑EDV by ↑force of contraction.

iii.Heart always functions on ascending limb of ventricular function curve

iv.What goes in, must come out.
- Cardiac output must equal venous return (on average)

97

Molecular basis of F-S law of the heart (3)

1) Cardiac titin isoform is very stiff, resists stretch past optimal length

2) Ca2+ sensitivity of myofilaments increases as sarcomeres are stretched

- Same intracellular Ca2+ produces a greater force of contraction

3) Longer sarcomere lengths change “lattice spacing” between actin and myosin, allows each cross bridge to generate more force

98

Describe relative changes in pressure and volume through the cardiac cycle (PV loop diagram)

Too busy to flashcard, draw that shit on your own! Not later, do it now!

99

SV=

EDV-ESV

100

Ejection fraction

fraction of EDV ejected during systole.

i.EF=SV/EDV= (EDV-ESV)/EDV

101

Stroke work

energy per beat (Joules), corresponds to area inside PV loop diagram.

NOT the same for the left and right sides of the heart

102

Pulse pressure

Peak systolic pressure at point E - End diastolic pressure at point D

103

Blood pressure

peak systolic / end diastolic

104

Preload

volume entering ventricles, pressure stretching ventricle prior to contraction

i.Equivalent to end diastolic volume (EDV)

105

Factors that affect preload (3)

1. Blood volume

2.Filling pressure and time

3.Resistance to filling

a.Right atrial pressure, AV valve stenosis

b.Ventricular compliance
- Slope EDPVR inverse of compliance (steeper slope, harder for ventricle to fill → lower EDV at any EDP)
- Hypertrophy reduces compliance
- Dilation increases compliance

106

Increase in preload ->

increase stroke volume for next beat → Starling’s law!

107

Afterload

resistance LV must overcome to circulate blood (wall stress)

108

Factors that affect afterload (3)

1. Aortic pressure (hypertension increases afterload)

2.Wall thickness and radius (Law of LaPlace)

3.Aortic stenosis

109

Increase in afterload →

decrease in stroke volume on next beat

1.Ventricle works harder against inc. aortic pressure → less blood ejected. ­

a.→ aortic valve opens later in cycle, reducing ejection time.

110

Contractility/inotropy

reflects strength of contraction at any given preload / afterload.

i.Force of contraction INDEPENDENT of fiber length

ii.Describes systolic function of heart

iii.Sympathetic tone is biggest factor affecting inotropy

iv. Changes in inotropy describe new ventricular function (Starling) curves.
- IF preload/afterload constant, and increase inotropy → new starling curve corresponds to greater systolic pressure for any given volume
- Increases stroke volume on the next AND SUBSEQUENT beats

111

Phases 0 of fast AP

RAPID UPSTROKE

-Rapid depolarization due to entry of Na+ through voltage activated Na+ channels (I-Na)

112

Phase 1 of fast AP

Phase 1: partial re-polarization

-inactivation of Na+ current

-activation of transient K+ channels

113

Phase 2 of fast AP

prolonged plateau

-voltage-activated L-type Ca2+ channels open

-Ca2+ influx balances K+ efflux (delayed rectifier channels - I-Kr and I-Ks)

114

Phase 3 of fast AP

rapid re-polarization

-inactivation of Ca2+ channels

-increasing activation of K+ channels (I-Kr and I-Ks)

115

Phase 4 of fast AP

cell held near Ek

-K+ channels deactivated

-Na+ and Ca2+ inactivation removed

-inward rectifier holds cell at Ek

116

What kinds of cells have fast cardiac APs

myocardial cells and cells of rapid conduction pathways

117

what kinds of cells have slow cardiac APs

found in pacemaker cells of SA and AV nodes

118

What makes slow cardiac APs different from fast cardiac APs (4)

1) reduced INa and little IK1
2) express If and ICa-T (absent in other myocardial cells)
3) NO partial repolarization (Phase 1)
4) NO prolonged plateau (Phase 2)

119

Phase 0 of slow AP

Slow Upstroke - ICa-T and ICa-L open, Ca2+ in

NO INa → slower upstroke

120

Phase 3 of slow AP

Repolarization

-ICa channels close

-delayed rectifier current (IKr and IKs) open

121

Phase 4 of slow AP

slow depolarization (pacemaker potential)

steady creep upward

NO STEADY RESTING POTENTIAL

122

Why is there no steady resting potential in slow APs?

1) slow deactivation of IKr / IKs and activation of ICa-T

2) FUNNY CURRENT, If (active at hyperpolarization) → upwards creep prior to generation of next AP

123

Sodium ion channel (I-Na)

Depolarization → activate rapidly → Na+ flows in → then inactivate

Activation and inactivation gate

-only present in fast AP

124

L-Type Calcium Channel (I-CaL)

-In ventricular and atrial myocardium, cells of SA/AV nodes, and conductive pathways.

-Activate rapidly in response to high voltage depolarization

-Voltage AND calcium dependent inactivation

-Currents blocked by dihydropyridines (DHPR) (anti-HTN agents)

125

T-Type Calcium Channel (I-CaT)

“LVA”—activated by weaker depolarization at low voltages

Currents activate and then inactivate in response to depolarization

Expressed in SA node and nervous system

126

Transient Outward K+ Channel (IKto)

Open during phase 1, causes partial repolarization

Makes voltage slightly more negative at plateau → more favorable for Ca2+ to come in (CRUCIAL)

Voltage-dependent inactivation

127

Rapid delayed rectifier (I-Kr) and Slow delayed rectifier (I-Ks) channels

Responsible for repolarization of both fast and slow APs

128

Inward rectifier channel (IK1)

-Inward current → no block, K+ easily flows into cell at VmEk

HELPS MAINTAIN RESTING POTENTIAL (NEAR EK) between APs

BUT does not fight ability of Na+ and Ca2+ channels to depolarize

Not gated in traditional sense.

129

GIRK I-K ACh channel

In pacemaker cells, regulated by ACh

Control frequency of pacemaker firing
ACh binds muscarinic receptor → Increased activation and current → slows HR

130

Funny current (If)

HC tetramer

Off at depolarized potentials, on at hyperpolarized potentials

Permeable to both Na+ and K+.

-responsible for slow creep upward during phase 4 of slow AP

131

Pacemaker potential

Generated by "funny current"

-slow upward creep of resting potential during slow AP

Critical to allow pacemaker cells to generate rhythmic firing in absence of neuronal input

Slow AP DOES NOT have a steady resting potential like fast APs

132

Overdrive suppression

AV node is active at a lower frequency than SA node

-AP spreads from SA node before AV cells reach threshold on their own

133

Ectopic pacemakers

cells that take over initiation of heartbeat when heart is damaged

134

Absolute refractory period

time following “fast” cardiac AP, a second AP cannot be initiated until most of the inactivation of INa is removed (during the repolarizing phase)

135

Relative refractory period

time following “fast” cardiac AP during which the threshold for a second AP remains elevated until after repolarization is complete

-Complete inactivation of INa and deactivation of IKr and IKs has occurred

136

Phase 0 corresponds to what part of ECG

-initial rapid upward deflection of R wave
-Due to fast sodium current

137

Phase 2 corresponds to what part of ECG

Isoelectric ST segment

Long plateau with little change in voltage (Ca2+ influx and K+ efflux balanced)

Links QRS to T wave

138

Phase 3 corresponds to what part of ECG

T wave

Repolarization ir occuring

Rapid decrease in voltage as K+ efflux continues

139

In what direction is the T wave on the ECG and why?

Repolarization (decreasing voltage) change in opposite direction from depolarization in Phase 0

BUT T wave and R wave in SAME direction on ECG

T wave repolarization and QRS complex should always be in same direction

Discordance is pathological → ischemia or ventricular hypertrophy

140

Phase 4 corresponds to what part of ECG

isoelectric segment after T wave

141

Electrical signal pathway in the heart (5 steps)

1) SA node pacemaker cells initiate electrical impulse (high in RA)

-Spread via cell to cell through gap junctions
-Depolarization sweeps downward and leftward
-Depolarization from endocardium to epicardium

2) → Depolarization through RA and LA = P wave

3) → AV junction → delay before depolarization enters ventricles → allows contraction of atria to end before ventricular contraction begins

4) → bundle of His into left and right bundle branches → bundles divide into fibers made up of Purkinje cells

-Right bundle: single entity, supplies RV primarily
-Left bundle: anterior and posterior branches serve LV

5) Purkinje cells radiate toward contractile cardiac myocytes → induce contraction

142

P wave represents...

depolarization of atria

143

QRS complex represents

depolarization of ventricles

Greater mass = greater voltage recorded

144

T wave represents

repolarization of ventricles

145

PR interval represents

index of conduction time across AV node

Plateau between P wave and initiation of QRS complex

Where depolarization pauses at bundle of His after depolarization of atria and before depolarization of ventricles.

146

QT interval represents...

total duration of depolarization and repolarization

Plateau after QRS complex and T wave, reflecting period of time between depolarization and repolarization of ventricles.

147

First degree AV block

conduction delayed but all P waves conduct to ventricles

Not typically harmful

148

Second degree AV block

some P waves conduct, others do not

149

Third degree AV block

no P waves conduct and a ventricular pacemaker takes over

Very bad - pacemaker cell takes over pacing but this is much slower than HR required for sufficient blood flow → must put in pacemaker

150

Left bundle branch block

QRS widening
Delayed conduction to LV

151

Left bundle branch black within one of the two fasicles causes...

→ change direction of depolarization, but does NOT cause widening of QRS

152

Right bundle branch block

QRS widening
Delayed conduction to RV

153

Three mechanisms of cardiac conduction disturbances that cause tachyarrhythmias

1) Abnormal reentry pathways
2) Ectopic foci
3) Triggered activity (afterpolarizations - early or delayed)

154

Ectopic foci

a focus of myocardium outside conduction system acquires automaticity

If rate of depolarization exceeds that in sinus node → abnormal rhythm

Can be isolated ectopic beats or sustained tachyarrhythmias

155

Long QT syndrome

-prolonged cardiac AP → ventricular arrhythmia, sudden death

-Prolongation of plateau phase of fast response AP in ventricular myocytes initiates ventricular tachycardia called torsades de pointes → subsequent syncope and sudden cardiac death.

-Can degenerate to V-fib

-Triggered by abrupt increase in sympathetic tone

156

Treatment of long QT syndrome

B-blockers

157

Gene defects of AD long QT syndrome (Romano-Ward) and their effect on current (3)

200 mutations associated with AD form (heterogenous)

1) Slow cardiac K+ channel, IKs (LQT1) → dec. K+ current

2) Rapid cardiac K+ channel, IKr (LQT2) → dec. K+ current

3) Cardiac Na+ channel, INa (LQT3) → incomplete I-Na inactivation → more inward Na+ current than normal

158

Molecular basis of Long QT syndrome mutation in K+ channel subunits

Mutations in cardiac K+ channel subunits (I-Kr, I-Ks) → reduce # of K+ channels expressed in myocyte plasma membrane (loss of function mutations)

→ Decreased K+ current → terminate plateau phase of fast response and return membrane to resting potential during diastole

159

Molecular basis of Long QT syndrome mutation in Na+ channel subunits

Mutations in myocyte Na+ channel (INa) → prevent Na+ channels from inactivating completely (gain of function mutations)

→ Prolong phase 2 of fast response.

160

Antiarrhythmic drugs:

Class I
Class II
Class III
Class IV

Class I = Na+ channel blocker

Class II = B-adrenergic receptor blockers

Class III = prolong fast response phase 2 by delaying repolarization by blocking K+ channel

Class IV = Ca2+ channel blockers

161

Class I drugs primarily act on _______ cells.

They decrease _____ and increase ______

fast response cells

Decrease conduction rate
Increase refractory period

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Class IA drugs has 3 major effects

1) Slow upstroke of fast response = slower conduction velocity (phase 0): block of Na+ channels (reduced I-Na)

2) Delay onset of repolarization: K+ channel block (class III effect)

3) Prolong refractory period (phase 4) because depolarization (phase 2) is prolonged.

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Class IC drugs 2 major effects

1) Pronounced slowing of upstroke of fast response (phase 0)

2) Mildly prolonged depolarization (phase 2)

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Class II drugs act to...(3)

These actions result in ______ and ______

1) Reduces rate of diastolic phase 4 depolarization in pacing cells

2) reduces upstroke rate

3) slows repolarization

→ Pacing rate reduced
→ Refractory period prolonged in SA and AV nodal cells

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Class III drugs act to...(2)

1) Prolongs fast response phase 2

2) Prominent prolongation of refractory period

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Class IV drugs act to...(2)

1) Slow Ca2+ dependent upstroke in slow response tissue (slow rise of AP)

2) Prolong refractory period (prolonged repolarization)

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Arrhythmias can be caused by (2)

1) Inappropriate impulse initiation (SA node or elsewhere (ectopic focus))

2) Disturbed impulse conduction (node, conduction/Purkinje cells, or myocytes)

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Early afterdepolarizations (EADs)

late phase 2 and phase 3

Dependent on re-activation of L-type Ca2+ channels in response to increased [Ca2+]in due to prolonged phase 2 (long QT)

→ move membrane potential towards ECa (depolarized)

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Delayed afterdepolarizations (DADs)

early phase 4

-Increased [Ca2+]in causes increased Na+/Ca2+ exchanger activity (NCX exchanger)

--> Electrogenic: 3 NA+ in, 1 Ca2+ out)

→ add positive charge inside myocytes = depolarization

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Re-Entry (Circus) Arrhythmia initiation requires what two conditions

1) Unidirectional conduction block in a functional circuit

2) Conduction time around circuit is longer than refractory period
-Cells have recovered from AP → they are able to fire another AP (you don’t want this)

-Arrhythmia triggered by afterdepolarizations but maintained by re-entry

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Use-Dependence

characteristic of Na+ channel blocking by Class I Antiarrhythmic drugs

Preferentially targets over-active cells or cells that have abnormally depolarized resting potentials

**Channel must be OPEN BEFORE it can be blocked

-Use-dependent drug holds channel in inactivated state much longer → Prevent re-entry!

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How do Class I antiarrhythmics prolong the refractory period

Class I drugs enter open channel but actually have a higher affinity for inactivated state of channel

→ use-dependent blockers stabilize inactivated state → prolong time channel spends in inactivated state

VITAL part of mechanism drugs use to suppress re-entrant arrhythmias

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How do B-Blockers suppress arrhythmias

B-blockers reduce Ih current, L-type Ca2+ current, and K+ current

→ reduces rate of diastolic depolarization in pacing cells, reduce upstroke rate and slow repolarization

→ Pacing rate is reduced and refractory period is prolonged in SA and AV nodal cells

B-blockers used to terminate arrhythmias that involve AV nodal reentry, and to control ventricular rate during atrial fibrillation.

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How do Class III drugs increase refractory period

Class III → block cardiac K+ channels

→ Prolongation of fast response phase 2

→ Prominent prolongation of refractory period due to prolonged duration of phase 2 leads to an increased inactivation of Na+ channels.

DIFFERENT from use-dependent mechanism of class I drugs

SIMILAR to secondary mechanism of increasing refractory period by class Ia drugs

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How do class IV drugs suppress reentry?

Slowing Ca2+ dependent upstroke in slow response tissue → slows conduction velocity (especially at AV node)

Prolonging refractory period → suppress reentry

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How can antiarrhythmic drugs suppress reentrant arrhythmias?

1) Convert unidirectional block to bidirectional block:
-Slow AP conduction velocity by reducing upstroke rate
-Slower conducting APs may not propagate through depressed region

2) Prolong refractory period:
-Refractory tissue will not generate AP → reentrant wave of excitation extinguished

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Antiarrhythmic drugs suppress arrhythmias by decreasing cardiac automaticity how?

Decrease cardiac automaticity, by decreasing rate at which a cell fires → ensures that cells do not generate their own “pacemaking” activity → suppresses arrhythmias

Class II (beta blockers) and Class III (K+ channel blockers) drugs are particularly good at this.

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Adenosine acts to...

1) reduce SA and AV node firing rate

2) reduce conduction rate in AV node

3) Increases K+ current

4) Decreases L-type Ca2+ current and If in SA and AV nodes

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Compare adenosine to B-blockers

Similar to beta-blockers but Adenosine is NOT a beta-blocker

Works via Gi-coupled receptor, which inhibits adenylyl cyclase and thus cAMP production