Cardiac Muscle Flashcards
1
Q
Specialized functional requirements of the cardiac muscle:
A
-must pump blood continuously: intrinsic pacemaker
-entire muscle must contract AND relax with each beat
(tetanic contraction would be fatal because the heart needs to refill) : gap junctions, conduction system, and prolonged AP
-must adapt quickly to changes in demand (exercise, trauma, infection, etc): contractility is modulated by preload/heart rate/beta adrenergic
2
Q
Intrinsic pacemakers
A
- needed for continuous pumping
- SA and AV node, no true resting potential and results in spontaneous action potential
3
Q
Synchronized contraction:
A
-needs efficient impulse conduction
-simultaneous activation of septum, RV, and LV free walls
(via HIs-purkinje network)
-gap junction and intercalated disks help
4
Q
AV Node
A
-impulse conduction is slower to allow for time for atrial contraction to fill the ventricles
5
Q
Gap junctions for efficient impulse:
A
-provide highly conductive electrical connections between adjacent cardiac myocytes
6
Q
Intercalated disks:
A
-provide mechanical and electrical junctions between cells arranged end to end
7
Q
How do myocytes prevent continuous stimulation
A
- via refractory period
- a long plateau phase and delayed repolarization produce prolonged period of absolute refractoriness to restimulation
- this prevents tetanic contraction
8
Q
Effects of faster stimulation frequency on action potential
A
- shortens the duration of the action potential so increased heart beat can occur despite refractory period
- refractory period could cause inability to have faster heart rate during stress but rate dependent shortening of AP duration bypasses this
9
Q
Cardiac muscle characteristics
A
- 1/2 nuclei per cell
- ANS
- connected electrically to adjacent cells
- partial activation NOT possible
10
Q
Calcium induced calcium release in cardiac muscles
A
- depolarization results in extracellular calcium influx (via L type voltage gated channel) close to the SR
- Ryanodine receptor on SR is calcium sensitive and triggers the release of much more intracellular calcium stores
- initiates contraction
11
Q
Steady state maintenance of calcium in cardiac muscle cells:
A
EXTRACELLULAR CALCIUM:
- calcium in via L type Ca Channel
- calcium out via Na/Ca exchanger
INTRACELLULAR CALCIUM:
- calcium released by SR (RyR)
- calcium reuptake via SR (SERCA)
12
Q
Cardiac Myosin II isoforms:
A
- 3 different isoforms V1 (max velocity of shortening is the highest) V2, V3 (shortest)
- 3 different isoforms because there are TWO myosin heavy chain forms (and 2 MHC/molecule)
13
Q
Passive muscle properties:
A
- as resting cardiac muscle is stretched, tension increases exponentially
- this is the tension due to connective tissue of the muscle
14
Q
Active muscle properties:
A
- increasing length increases tension (force)
- this is the tension due to the interaction of myosin and actin
15
Q
Starling’s Law of the heart:
A
- increasing the blood to the heart stretches the ventricle (increase length) which results in more forceful ejection (increased tension)
- the heart pumps out the volume of blood it receives (more blood when exercising)
- relationship between end-diastolic volume and cardiac ejection volume (beat by beat basis)
16
Q
Diastole:
A
- relaxation, refilling with blood
- mitral valve opens, inflow to left ventricle
- end of diastole volume/pressure is greatly increased
17
Q
Systole:
A
-contraction, volume decreases
18
Q
Cardiac muscle length-tension
A
- cardiac muscle has a greater resistance to passive stretch (very stiff when sarcomere length is above or below maximal active force development)
- the curve has little or NO descending limb
19
Q
Isometric versus isotonic:
A
- isometric: contraction of the left ventricle when all the valves are closed (no muscle shortening)
- isotonic: contraction of the ventricle as blood is forced into the aorta, against pressure
- isometric l/t curve provides limit for the isotonic performance *same final tensions
20
Q
Frank-Starling Mechanism:
A
-positive relationship between sarcomere length and developed tension
21
Q
Mechanisms contributing to Starling’s Law
A
- increasing the number of possible cross-bridges (more favorable position on the length-tension curve)
- calcium sensitivity of contraction is length dependent
- calcium release is length dependent
22
Q
Length and Calcium sensitivity
A
relationship between intracellular calcium concentration and isometric force is positive
-as length increases there is an increase in calcium sensitivity (increase in force for the same calcium concentration)
23
Q
Force response and calcium release:
A
- cardiac cells can alter force responses to a given level of calcium release by:
- length dependent calcium affinity of the troponin complex (increase length, increase affinity)
-neuro-endocrine modulation:
Phosphorylation of TnI, RLC, C-protein, phospholamban
24
Q
Impact of afterload on performance:
A
- afterload is Vmax
- increasing afterload tends to restrain the contractile performance and reduce contractile efficiency
25
Efficiency:
amount of shortening (work x tension) per unit of energy consumed
26
Series elastic element:
- during initial muscle contraction, forces related to series elastic elements must be overcome before there can be external shortening (work) - at this time there is no increase in force though (afterload)
- sources: titin or extracellular matrix collagen
27
Force-frequency response (Treppe)
cardiac force is a function of the calcium concentration and therefore, stimulation frequency
-as the interval between stimuli decreases, the force increases
28
Positive force-frequency response:
- normal heart
| - increase in force as the stimulation rate increases
29
Negative force-frequency response:
- failing heart
| - force does not increase as stimulation frequency increases
30
How does increased frequency increase force?
- increased stimulation rate increases calcium influx via L-type channel
- SERCA and NCX (Na/Ca pump out of the cell) compete for the increase in calcium
- SERCA > NCX then INCREASED CONTRACTILITY (positive response)
- SERCA < NCX then DECREASED CONTRACTILITY (negative response)
31
Cardiac responses to B1 adrenergic stimulation:
- stimulates sinus node and increases heart rate which increases contractility (force-frequency)
* more beats
- B1 mediated phosphorylation of L-type channel, phospholamban, and RyR all favor larger calcium concentration inside the cell and increased systolic force generation
* stronger beats
- phosphorylation of phospholamban and troponin I/T favor faster relaxation, required with faster beat
* faster relaxation
-IE: more beats, stronger beats, faster relaxation = increased cardiac output
32
Effect of increased sympathetic stimulation:
- increase rate of pressure development
- increase rate of relaxation
* during Beta adrenergic stimulation there is DECREASED sensitivity to calcium
33
Adrenergic Modulation of myocardial contractility:
- marked increase in the peak intracellular calcium
- increase rate of rise/fall of intracellular calcium
- increase peak force, rate of force development, and increase relaxation
- ratio of peak calcium concentration to peak force decreases
- inotropy (contractility independent of preload/afterload): positive ionotropic stimulus (left and up shift of length tension - more contractility)
34
What does increasing preload do:
increases active tension
increases passive force
*little effect on relaxation
35
What does increasing afterload do:
reduces the extent/rate of shortening
variable effect on relaxation
36
What does increasing stimulation frequency do:
increases force development
increases relaxation rate (shorter action potential)
37
What does increasing adrenergic stimulation do:
increases force development
increases rate of relaxation
38
Cardiac Cycle:
diastolic filling (p-wave)
isovolumetric contraction: (QRS)
Ejection: intraventricular pressure is greater than aortic pressure) (t wave = repolarization and relaxation) Once pressure no longer greater, valves close
isovolumetric relaxation: pressure continues to decrease, mitral and aortic valves are closes
*once the atrial pressure begins to exceed ventricular again, mitral valve opens and diastolic filling restarts
39
Isovolumetric contraction:
- ventricular depolarization leads to force production
| - mitral valve closes, pressure increases (volume stays the same) and ejection begins
40
Cycle summary:
LV pressure falls below atrial pressure and mitral valve opens -> ventricle fills -> mitral valve closes -> isovolumic contraction -> ejection when LV exceeds atrial and aortic valves open -> continues until atrial is higher again, relaxation starts before this pressure and causes aortic valve to close. Repeat.
41
Preload:
volume filling the LV chamber
42
Afterload:
aortic pressure that must be overcome to initiate ejection
43
Cardiac contraction is:
- myogenic - each contraction is not initiated by nervous input (all the nerves to the heart could be severed and it would still beat)
- syncytium: all cells electrically connected and all cells contract together (unlike skeletal where you can increase the number of cells to increase contractility)
44
Phases of cardiac action potential:
Phase 0: upstroke, Na
Phase 1: initial repolarization, inactivation of Na channels and brief K out
Phase 2: plateau, Ca channels slowly inactivate and delayed rectifier K channels activate
Phase 3: rapid repolarization, inactivation of Ca channels and inward rectifier and delayed rectifier activation of K (return to Vm)
Phase 4: resting potential (more permeable to K so Vm close to Ek)
45
Ions with large concentrations outside the cell:
Na and Ca
produce INWARD ionic currents
46
Ions with large concentrations inside the cell:
K
produce OUTWARD ionic currents
47
K Channels
6 transmembrane helices
GYG sequence in ionic pore selects K ions in preference to others
48
Na Channels
- active gate opens between -70 and -20 mV
- inactivation gate closes between -80 and -40 mV
- as resting potential is depolarized, less inactive gates (at plateau most Na channels inactivation so plateau dictated by Ca channels instead)
49
Heart Ca channels mediate:
- upstroke of SA and AV nodal AP
- plateau of all AP
* four groups of 6 transmembrane segments like Na channels
50
T Type Ca Channels:
- activate between -80 and -40
- inactivate quickly
- SA and AV nodes, generate spontaneous AO
- transient
51
L Type Ca Channels:
- active between -30 and 0
- inactivate slowly
- blocked by Ca antagonists
- carry the plateau of the AP
- long lasting
52
Rapid Na Current:
- Na current supports conduction in working myocardium (ie) ventricular, atrial
- not operative in SA and AV node (specialized conducting tissue)
- supports rapid conduction in Purkinje and His
53
Slow Ca Current:
- underlies plateau and activates contraction in working myocardium
- generates upstroke and allows propagation in specialized conducting tissues
- underlies plateau and also may allow slow responses when Na reduced in Purkinje and His
54
Inward rectifier:
- one of the K channels in the heart
- resting conductance
- high conductance at negative potentials stabilizes resting potential
- off during the plateau
- conductance (ion flow) is higher for inward currents than outward at negative Vm (K flows in to stabilize Vm near EK)
55
Delayed Rectifier:
- activates very slowly at positive potentials (plateau)
| - partially responsible for terminating plateau and for final repolarization
56
Absolute refractory period:
second response not possible regardless of strength or duration of stimulus
57
Relative refractory period:
a second response can be elicited but at a greater cost
58
Working myocardial fibers:
atria and ventricles
strongly contractile
stable diastolic potential (true resting potential)
fire AP when stimulated
59
Pacemaker cells versus working cardiac:
- SA small
- less inward rectifiers
- Ach induced current (working cardiac doesnt have)
- less L type
- well developed T type
- poorly developed Na channels
60
Pacemaker activity of the SA node:
due to the combined effects of deactivation of K current (determines max diastolic potential -- delayed rectifier), activation of nonselective (Na and K) pacemaker current (funny current), and Ca current (slow upstroke of the AP)
-innervated by sympathetic and parasympathetic neurons
61
diastolic potential:
most negative Vm reached during diastole
-determined by Ik
62
Electrical connections between cardiac cells:
gap junctions at intercalated disks and later borders
- 6 connexin monomers per gap junction in EACH membrane
- 6 connexins/connexon
- 2 connexons/bilayaer membrane
63
Propagation and generation of extracellular potentials
- local circuit currents
- current flows from active region (+) to inactive (-) mainly by K ions inside the cells and between them via gap junctions
- return circuit flows through the extracellular space via Na and Cl
- current into the active tissue via Na and Ca currents that activate AP
64
size of wave in EKG
= magnitude of net current flow
-more cells, bigger waves
65
Polarity of wave
-net direction of current flow, time dependent
66
length of wave
-duration of event
67
P wave
atrial depolarization
68
QRS Complex
ventricular depolarization
69
T wave
ventricular repolarization (from epicardium to endocardium)
70
PR Interval
first atrial depolarization to first ventricular depolarization
Conduction through atria, AV, His Purkinje
71
QT Interval
- first ventricular depolarization to LAST repolarization
| - this interval is longer because ventricular depolarization is longer and there are more cells here
72
Do you see atrial repolarization?
-no, washed out by QRS
73
ST segment
-AP plateau phase 2
74
Increased QT Interval
increased AP duration
lengthened plateau phase
occurs due to:
- increased depolarization current due to increased inward Na current or decreased Na inactivation
- decreased repolarization current due to decreased outward K current or decreased K function
75
Drug Induced QT
- decreased IKs = long QT1 and can be mimicked by drugs that black the delayed rectified current
- LQT3 - increased Na channel, very prolonged ST segment
76
Inherited LQT
- LQT1 (decreased IKs) -LOF
- LQT2 (decreased IKr) -LOF
- LQT3 (increased Na) -GOF *tend to be worse
* all have similar EKG
77
How does LQT occur?
- after depolarization
- unexpected increase in depolarizing current
- imbalance of K/Ca currents during plateau/repolarization
- may produce second AP (can cause extra heartbeat)
78
Types of depolarization issues in LQT
- early EAD phase 2, 3: due to reactivation of L type Ca Channels
- delayed DAD phase 4
79
Arrhythmia mechanisms of LQT
-baselined prolonged QT -> early after depolarizations -> polymorphic VT -> systole
80
Leads
L1: LA - RA
L2: LL RA
L3: LL -LA
81
V1 - 6
- have standardized positions on the patient
| - record the vectorial flow of excitation and repolarization in the horizontal plane
82
Excitation Coupling overview:
1) Ca transient: depolarization of the membrane by AP leads to an increase in myoplasmic Ca via L type. Ca then binds to RyR opening them and more Ca flows in from the SR (Ca induced Ca release) Ca then declines
83
cardiac myocyte structure
- myofibrils similar to skeletal
| - plasmalemma folds into T tubules (larger than skeletal)
84
Membranes involved in EC coupling
- t tubules: coupled with SR vesicles to form dyads
- peripheral junction: subsarcolemmal cisternae (SR vesicles) form junctions with the surface membrane
- feet: RyR ca channel
85
Synonym for L type ca channel
-DHPR because they bind DHP Ca antagonists like niphedipine
86
Cross bridge cycle of cardiac myofibrils:
- thin filament (actin) switched on myosin heads attach and slide - slide - detach - repeat many times during contraction
* team rowing (myosin head is the oar)
87
Regulation of the thin filament:
- tropomyosin blocks myosin from attaching to actin at rest
- with increase Ca, troponin C binds to topomyosin and move it from myosin binding site
- myosin attaches and splits ATP to shorten the muscle
88
Cardiac muscle relaxation:
-ICa stops when the AP repolarizes
Calcium removal:
- Ca pump removes on SR membrane using ATP
- Na/Ca 3 Na in 1 Ca out
* Na and K that translocated during AP also returned (3 Na out, 2 K in)
- ATP restored by rephosphorylation of ADP by creatine phosphokinase CPK and oxphos
89
Alterations in pacemaking cells that change heart rate:
- diastolic interval of SA node is predominant control
- this can be changed by:
1) changing the rate of diastolic depolarization
2) threshold voltage of the AP
3) max diastolic potential
90
Positive chronotropic effect:
- 2 catecholamine hormones increase heart rate by increasing the ICa and increasing diastolic depolarization
- n-epi from sympathetic nerve endings near SA and AV node
- epi from adrenal medulla
* also increase Na/K pump
91
Beta blockers
-sympathetic agonists (catecholamines) increase heart rate, therefore, a blocker decreases heart rate
92
beta pathway
beta receptor is GPCR
- bind -> g protein activated -> adenylyl cyclase active -> cAMP -> cAMP dependent kinase -> phosphorylation of Ca channel
* goes backwards when dissociated
93
Parasympathetic Action on SA node:
- ACh
- from vagus nerve decreases heart rate by increasing K permeability
- GPCR bind to ACh and opens K channel -- no second messenger
94
3 alterations in strength of contraction:
- increased calcium
- more sensitive to calcium
- more force at each calcium concentration
95
Rate staircase:
- rate and rhythm of beating directly influence strength of contraction
- raising frequency raises strength *doesn't depend on the catecholamines
96
How does contraction strength increase at higher rates?
- because diastole shortens more than systole (longer time in systole), this means that more calcium can enter the cell during the action potential and less leaves during the diastolic interval (which is shorter)
- relaxation is faster, as is contraction
* SHORTER, HIGHER CONTRACTION
97
myofibril Ca/length relationship
- more sensitive to Ca at longer lengths (left shift)
| - max tension increase (higher peak) because cross bridges capable of generating more force at longer length
