CV Week 1a Flashcards
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
The heart is a _____ pump. Two sides work _________ but there is NO __________
dual
in parallel
direct connection between them
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
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
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
The right and left side of the heart are arranged in ________
series
Layers of the hear from inside to outside (4)
1) Endocardium
2) Myocardium
3) Epicardium
4) Pericardium containing pericardial fluid
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
Atrioventricular valves
Tricuspid and mitral
-between atria and ventricles
-Attached to papillary muscles inside ventricles by chordae tendonae
(Prevents prolapse of valves)
Tricuspid valve
between right atrium and the right ventricle
Mitral valve
between left atrium and left ventricle
BICUSPID
Semilunar valves
Aortic and pulmonic valves
- Between ventricles and great arteries
- NO chordae tendons
Pulmonic valve
between right ventricle and pulmonary artery, tricuspid
Aortic valve
between left ventricle and aorta, tricuspid
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
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
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
Aorta
single outlet from heart; d=2.5 cm.
Elastic and smooth muscle fibers in walls dampen pulsatile flow
Arteries
thick walled, resist expansion, d=0.4 cm
Distribute blood to different organs
Arterioles
relatively thick walls (lots of vascular smooth muscle); d = 30 um.
Highly innervated → primary site of regulation of vascular resistance.
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)
Capillaries
smallest vessels
Walls are single layer of epithelium (approx same size as RBCs), d = 6 um
Exchange vessels
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
Vena cava (inferior and superior)
two branches that input to heart; d=3 cm
Large diameter, but very thin wall
Very low pressure
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
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
Flow equation
Q = ΔP/R
Q = flow (ml/min) ΔP = pressure difference R = resistance
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
↓ vascular resistance = _____ flow
↓ vascular resistance = ↑ flow
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)
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
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
Radius effect on flow
**Radius of vessel has HUGE effect (to 4th power) on flow
increase viscosity = ______ flow
DECREASE
Increase length = ______ flow
DECREASE
Pulsatile flow
heart pumps intermittently, creating a pulsatile flow in aorta
Pulsatile flow requires more work
Analogy: stop and go driving requires more gas
Systolic vs. Diastolic
Systole vs. Diasatole
Systolic = peak aortic pressure Diastolic = minimum aortic pressure
Systole = contraction Diastole = relaxation
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.
Mean arterial pressure (MAP)
Diastolic pressure + (⅓) x (systolic pressure - diastolic pressure)
Vascular compliance equation
C=ΔV/ΔP
change in volume/change in pressure
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
Ateriosclerosis
loss of compliance caused by thickening and hardening of arteries
*Some arteriosclerosis is normal with age
NOT the same as atherosclerosis
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
Decreased wall thickness = ______ tension
increased
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
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
Hydrostatic pressure promotes _________
FILTRATION (movement of fluid out of capillaries)
Oncotic pressure promotes ________
REABSORPTION (movement of fluid into capillaries)
Hydrostatic pressure (P)
fluid pressure
Net hydrostatic P in capillary bed = capillary pressure - interstitial pressure
Solvents move from high pressure to low pressure.
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.
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)
You can get excess filtration due to _____ or ________.
Excess filtration causes ________
Increased BP (HTN) or reduced oncotic pressure (liver disease)
EDEMA in tissues
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
Net flux is primarily controlled by ________
control of capillary hydrostatic pressure
Vasoconstriction / vasodilation of arterioles
Net flux is different in different capillary beds
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)
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
Myosin
two heavy chains and four light chains = thick filament
Actin
similar to skeletal muscle actin; binds tropomyosin and troponin.
Thin filaments - length does NOT change, slides across mysoin
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)
TN-C
Thin filament regulatory protein (troponin)
calcium binding, contains only one Ca2+- binding site.
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
TN-T
Thin filament regulatory protein (troponin)
- binds tropomyosin, regulates calcium-sensitivity
- Isoforms are developmentally and pathologically regulated.
Tropomyosin (TM)
overlays actin blocking myosin binding site
only alpha isoform in cardiac muscle cells (skeletal muscle has alpha and beta)
cardiac muscle cell at rest
low intracellular Ca2+, TN-™ complex inhibits actin-myosin combination
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
Cardiac muscle cell relaxation
Calcium released, TM re-blocks binding site → relaxation
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
Length-tension relationship is responsible for the regulation of _______
pre-load
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
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
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
Frank-Starling Law
Increased in preload leads to an increase in stroke volume
Factors that effect stroke volume (3)
1) Preload
2) Afterload
3) Contractility of myofilament
Preload
initial length of myocyte, sets length-tension relationship
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
Increased tension of cells in heart wall –> ?
increased intraventricular pressure
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
Contractility of myofilament is primarily determined by __________
calcium sensitivity
Cardiac output (CO) = ?
stroke volume x heart rate
Volume of blood pumped per minute by LV
CO at rest
4-6 L/min
- can be increased by up to eight fold during strenuous exercise
Stroke volume (SV)
volume of blood pumped per beat
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)
4 phases of cardiac cycle
- Filling phase
- Isovolumetric contraction phase
- Ejection phase
- Isovolumetric relaxation phase
Filling phase
end of diastole, LA filled with blood from pulmonary vein
1.Contraction triggered by electrical signal that originates at SA node
- As atrium begins to contract, atrial pressure increases.
- ↑ atrial pressure
- .no change in volume - “The A wave” in both atrial pressure and ventricular pressure = atrial systole
- Mitral valve OPEN → blood flows freely into ventricle as atrium contracts
Isovolumetric contraction phase
- Wave of depolarization reaches ventricle → begins to contract, ↑ ventricular pressure
- Initial increase in pressure pushes mitral valve closed
- Ventricular pressure quickly exceeds that in the atrium. - 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
Ejection phase
ventricle continues to contract, ventricular pressure exceeds that in the aorta → aortic valve pushed open, blood begins to flow
- ↓ ventricular volume
- ↑ and then ↓ in ventricular pressure.
Isovolumetric relaxation phase
ventricle begins to relax, ↓ventricular pressure
- Ventricular pressure drops below aortic pressure → aortic valve closes
- Ventricle continues to relax with both valves closed → pressure falls rapidly. - Ventricular pressure ↓ slowly at first and then rapidly.
- Ventricle continues to relax, pressure eventually falls below that in atrium → mitral valve opens, blood flow into ventricle begins new cycle
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
Summary of pressure changes in cardiac cycle (3)
- 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)
- 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.
- 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.
Pressure and volume changes in the left ventricle are bounded by two curves:
Systolic and End Diastolic Pressure-Volume Relation
End-diastolic pressure volume relationship (EDPVR):
pressure-volume relationship during filling of heart BEFORE contraction
i.Passive elastic properties of ventricle (compliance)
High compliance = ____ slope of EDPVR
Shallow
- Not much change in pressure with an increase in volume
- Some pathologies ↓ compliance, making EDPVR steeper, impairing ventricle.
EDVPR represents ____ on left ventricl
preload
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.
Active tension
difference in force between peak systolic pressure and end diastolic pressure (tension developed by contraction)
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)
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
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!
SV=
EDV-ESV
Ejection fraction
fraction of EDV ejected during systole.
i.EF=SV/EDV= (EDV-ESV)/EDV
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
Pulse pressure
Peak systolic pressure at point E - End diastolic pressure at point D
Blood pressure
peak systolic / end diastolic
Preload
volume entering ventricles, pressure stretching ventricle prior to contraction
i.Equivalent to end diastolic volume (EDV)
Factors that affect preload (3)
- Blood volume
- Filling pressure and time
- 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
Increase in preload ->
increase stroke volume for next beat → Starling’s law!
Afterload
resistance LV must overcome to circulate blood (wall stress)
Factors that affect afterload (3)
- Aortic pressure (hypertension increases afterload)
- Wall thickness and radius (Law of LaPlace)
- Aortic stenosis
Increase in afterload →
decrease in stroke volume on next beat
- Ventricle works harder against inc. aortic pressure → less blood ejected.
a. → aortic valve opens later in cycle, reducing ejection time.
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
Phases 0 of fast AP
RAPID UPSTROKE
-Rapid depolarization due to entry of Na+ through voltage activated Na+ channels (I-Na)
Phase 1 of fast AP
Phase 1: partial re-polarization
- inactivation of Na+ current
- activation of transient K+ channels
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)
Phase 3 of fast AP
rapid re-polarization
- inactivation of Ca2+ channels
- increasing activation of K+ channels (I-Kr and I-Ks)
Phase 4 of fast AP
cell held near Ek
- K+ channels deactivated
- Na+ and Ca2+ inactivation removed
- inward rectifier holds cell at Ek
What kinds of cells have fast cardiac APs
myocardial cells and cells of rapid conduction pathways
what kinds of cells have slow cardiac APs
found in pacemaker cells of SA and AV nodes
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)
Phase 0 of slow AP
Slow Upstroke - ICa-T and ICa-L open, Ca2+ in
NO INa → slower upstroke
Phase 3 of slow AP
Repolarization
- ICa channels close
- delayed rectifier current (IKr and IKs) open
Phase 4 of slow AP
slow depolarization (pacemaker potential)
steady creep upward
NO STEADY RESTING POTENTIAL
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
Sodium ion channel (I-Na)
Depolarization → activate rapidly → Na+ flows in → then inactivate
Activation and inactivation gate
-only present in fast AP
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)
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
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
Rapid delayed rectifier (I-Kr) and Slow delayed rectifier (I-Ks) channels
Responsible for repolarization of both fast and slow APs
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.
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
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
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
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
Ectopic pacemakers
cells that take over initiation of heartbeat when heart is damaged
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)
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
Phase 0 corresponds to what part of ECG
- initial rapid upward deflection of R wave
- Due to fast sodium current
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
Phase 3 corresponds to what part of ECG
T wave
Repolarization ir occuring
Rapid decrease in voltage as K+ efflux continues
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
Phase 4 corresponds to what part of ECG
isoelectric segment after T wave
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
P wave represents…
depolarization of atria
QRS complex represents
depolarization of ventricles
Greater mass = greater voltage recorded
T wave represents
repolarization of ventricles
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.
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.
First degree AV block
conduction delayed but all P waves conduct to ventricles
Not typically harmful
Second degree AV block
some P waves conduct, others do not
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
Left bundle branch block
QRS widening
Delayed conduction to LV
Left bundle branch black within one of the two fasicles causes…
→ change direction of depolarization, but does NOT cause widening of QRS
Right bundle branch block
QRS widening
Delayed conduction to RV
Three mechanisms of cardiac conduction disturbances that cause tachyarrhythmias
1) Abnormal reentry pathways
2) Ectopic foci
3) Triggered activity (afterpolarizations - early or delayed)
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
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
Treatment of long QT syndrome
B-blockers
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
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
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.
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
Class I drugs primarily act on _______ cells.
They decrease _____ and increase ______
fast response cells
Decrease conduction rate
Increase refractory period
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.
Class IC drugs 2 major effects
1) Pronounced slowing of upstroke of fast response (phase 0)
2) Mildly prolonged depolarization (phase 2)
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
Class III drugs act to…(2)
1) Prolongs fast response phase 2
2) Prominent prolongation of refractory period
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)
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)
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)
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
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
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!
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
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.
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
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
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
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.
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
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
