Physiology Flashcards
5 general features of cardiac muscle
Myogenic Striated Cells electrically coupled Mainly oxidative metabolism AP triggers calcium-induced calcium release
Main cell types of myocardium
Cardiac fibroblasts Myocytes Endothelial cells Vascular smooth muscle cells Neurons
Function of cardiac fibroblasts
Secrete and maintain connective tissue fibres
Majority of cells in the heart
Function of myocytes
Provide majority of myocardial mass
Carry out contraction
Can be specialised e.g. purkinje and nodal cells
About 30% of heart cells - 20 microns thick and 100 microns long
Things you will see in a longitudinal section of myocardium
Striations
Endocardial spaces containing collagen
Intercalated discs at intercellular junctions
3 types of junction in the heart
Gap junctions
Intermediate junctions
Desmosomes
Extracellular matrix composition
60% vascular 23% glycocalyx-like substance 7% connective tissue cells 6% empty space 4% collagen
Sarcolemma
Forms a permeability barrier between the inside and outside of the cell
Continuous with t-tubules
Glycocalyx
Outer surface of sarcolemma abundant in acidic mucopolysaccharides and sialic acid residues
Divided into surface coat and external lamina
T-tubules
Invaginations of sarcolemma
Rich in L-type calcium channels (DHPRs)
Bigger than in skeletal muscle
Caveolae
Small invaginations of sarcolemma Scaffolding proteins (cavoelin-3) and signalling molecules (NOS and PKC) found here
Sarcoplasmic reticulum
Intracellular membrane-bound compartment
Internal calcium store
Junctions with t-tubules and external sarcolemma
Junctional sarcoplasmic reticulum contains ryanodine receptors or calcium release channels
Contains SERCA and calseqeuestrin
SERCA
Sarcoplasmic reticulum calcium ATPase
Responsible for re-uptake of calcium into sarcoplasmic reticulum
Phospholamban modulates activity
Calsequestrin
Calcium buffer (calcium sequester)
Excitation-contraction coupling
The process by which electrical changes at the surface membrane lead to changes in intracellular calcium levels which activate contraction
5 steps of EC coupling
1) AP from adjacent cell spread across sarcolemma
2) Depolarisation opens L-type calcium channels
3) Calcium influx opens ryanodine receptors causing sarcoplasmic reticulum calcium release
4) Calcium ions bind to TnC and initiate crossbridge cycling
5) Contraction
Calcium-induced calcium release
DHPRs form functional voltage-gated calcium channels in cardiac muscle
Depolarisation opens channels and influx of calcium triggers further calcium release from sarcoplasmic reticulum via ryanodine receptors
2 sources of calcium to activate contraction
1) extracellular
- voltage dependent calcium channels in the sarcolemma membrane
- passive leakage channels in the sarcolemma
2) intracellular
- sarcoplasmic reticulum
- mitochondria
L-type calcium channels (DHPRs) stimulation
Catecholamines
Depolarisation
L-type calcium channels (DHPRs) function
Carries inward calcium current
Contributes to AP plateau
Triggers EC coupling
L-type calcium channels (DHPRs) inhibition
Sarcoplasmic reticulum calcium release
Calcium channel blockers
Magnesium
Low plasma calcium concentration
High sarcoplasmic reticulum calcium load leads to:
Increased calcium available for release
Enhanced gain of EC coupling
Microscopic sarcoplasmic reticulum release events
Calcium sparks - summate to make the whole cell calcium transient
Amplitude and number of calcium sparks determines the calcium transient amplitude
Myocyte relaxation
Occurs when intracellular calcium concentration is reduced and calcium unbinds from TnC
Bulk of calcium pumped back into sarcoplasmic reticulum for storage
Small amount leaves cell in exchange for sodium
4 important calcium transport proteins
SERCA (calcium into sarcoplasmic reticulum)
SELCA (calcium out of cell)
NCX (calcium out of cell, sodium in)
Mitochondrial uniporter (calcium into mitochondria)
If calcium efflux is decreased:
Calcium accumulates in cell leading to
- higher sarcoplasmic reticulum calcium content
- increased calcium extrusion to balance influx
SELCA pump
Sarcolemma calcium ATPase pump
Minor contributor to calcium extrusion at rest
Electroneutral - brings protons into cell
Electrogenic sodium calcium exchanger
Reverse mode (calcium entry) follows depolarisation Forward mode (calcium exit) promoted by repolarisation Contributes to myocyte membrane potential, both depend on electrochemical gradient
Two ways that calcium can be removed from the cytoplasm
1) Extrusion across the sarcolemmal membrane
2) Sequestration into the sarcoplasmic reticulum
3 properties of cardiac myocytes
Excitability
Conductivity
Automaticity
Cells with a fast excitability response
Atrial cells
Ventricular cells
Fast parts of specialised conduction system
General fast response action potential
Phase 0: Rapid depolarisation Phase 1: Early repolarisation Phase 2: Plateau Phase 3: Repolarisation Phase 4: Resting
Phase 0 key points
-90 mV resting potential to -70 mV threshold potential
Rapid increase in sodium permeability causes fast inward sodium current
Causes upstroke
Phase 1 key points
Early repolarisation to near 0 mV
Transient outward potassium current
Phase 2 key points
Sodium channels inactivate
Cell becomes refractory
Inward and outward currents nearly balanced
Slow inward calcium current and outward potassium current
Phase 3 key points
Outward potassium currents
- iK switched on after delay
- iK1 reactivated as membrane potential drops
- iK,ATP activated when ATP drops
- iK,ACh activated when ACh drops
Phase 4 key points
iK1 high potassium conductance defines resting potential
Timespan of fast response AP
Phases 0 - 1 = about 10 msec Phases 1 - 2 = about 100 msec Phases 2 - 3 = about 150 msec Phases 3 - 4 = about 50 msec Overall, about 290 - 310 msec
Ions of calcium pump
Outward current
Ions of Na/Ca exchanger
Ongoing
3Na in, 1 Ca out
Electrogenic
At resting potential, current is inward and depolarising
Ions of Na/K ATPase
3Na out, 2K in
Electrogenic
Current is outward and repolarising
Slow response cells are driven by:
Calcium, not sodium
2 reasons by slow response cells might not be driven by sodium
1) sodium channels already inactive
2) no sodium channels present
Slow response cell locations
SA node
AV node
Slow response cell key points
Can be pacemaker or non-pacemaker
Resting potential around 55 mV
Similar to fast response but phase 0 is slow upstroke due to slow inward calcium current
4 refractory periods
1) Absolute refractory period
2) Relative refractory period
3) Supranormal period
4) Full recovery time
Absolute refractory period
Time when membrane cannot be re-excited
Relative refractory period
Need larger than normal stimulus to get propagated AP (slow propagation)
Supranormal period
Get propagated AP from weaker than normal stimulus (slow propagation)
Full recovery time
May extend beyond return to resting potential
Time dependent
Refractoriness over long periods advantage
Prevents tetanising of heart
Interval-duration relationship
Duration of action potential is determined partly by preceding diastolic interval
Rapid heart rate = shorter AP
Related to properties of various ion channels
Conductivity of cardiac muscle cells
Myogenic, not neurogenic
Do not contract in response to neural signal
All cells interconnected
Electrical activation spreads through myocardium from cell to cell
Due to electrical coupling between neighbouring cells
Pacemaker cells
SA node
Some cells around AV node
His-Purkinje network
Automaticity
Ability to initiate electrical impulse through own pacemaker activity or diastolic depolarisation
Pacemaking is based on:
The membrane slowly depolarising in phase 4
3 mechanisms for altering intrinsic rate of pacemaker discharge
Alter rate of depolarisation
Alter threshold potential
Alter maximum diastolic potential
Funny current
Mainly inward sodium current
Activated at negative potentials when the cell has repolarised
Some K+ current
Conduction velocity of SA node
Less than 0.01 m/s
Conduction velocity of AV node
0.02 - 0.05 m/s
Conduction velocity of bundle branches and purkinje network
2.0 - 4.0 m/s
AV delay is due to:
Slow conduction in the AV node
Activation subject to block because of this
ECG
Sum of electrical activity of heart
Voltage over time recording
Electrodes measure potential difference between different sites on the body caused by the electrical activity of the heart
ECG electrodes don’t need to be on the heart because:
Body tissues act as conductors
3 main deflections on ECG
P wave - atrial depolarisation
QRS complex - ventricular depolarisation
T wave - ventricular repolarisation
P wave
Atrial depolarisation
Relatively small mass therefore small height deflection
Slow, therefore wide
PR segment
Isoelectric
Reflects time taken for wave to pass through AV node, AV bundle and bundle branches
QRS complex
Ventricular depolarisation
Greater magnitude than P wave due to greater mass of tissue
Relatively shorter than P wave because of rapid spread to Purkinje fibres
Atrial repolarisation present, but not visible
PR interval
Reflects total time for wave to pass from atria to ventricles
ST segment
Isoelectric
All depolarised therefore no moving wavefront
Plateau of ventricular AP
T wave
Asynchronous ventricular repolarisation
Slower than depolarisation
QT interval
Reflection of ventricular action potential duration
3 things that affect electrode recording
Magnitude of charges
Orientation of dipole and electrodes
Distance between dipole and electrodes
Q wave
Ventricular septum depolarising
R wave
Ventricular apex depolarising
S wave
Ventricular base depolarising
T wave orientation
Ventricular depolarisation is endocardium to epicardium, therefore +ve QRS
Ventricular repolarisation is epicardium to endocardium, therefore +ve T wave
Limitations of ECG
Body has varying conductivity
Single dipole not good representation of wavefront
Bipolar system
Measures difference between two electrodes
Three bipolar limb leads
Lead I = LA - RA
Lead II = LL - RA
Lead III = LL - LA
Einthovens law
Equivalent to connecting the electrodes to 3 corners of an equilateral triangle with the heart at the centre
At any instant during the cardiac cycle, I + III = II
Three augmented unipolar limb leads
aVR, aVL, aVF
Unipolar chest leads
V1 - V6
Look at heart from front and side in the horizontal plane
Calibration signal is always:
1 mV
Normal QR axis values
-30 to +110 degrees
0 degrees = horizontal
Calculation of mean QRS vector
Biggest +ve minus biggest negative (both from 0)
EC coupling summary
Depolarisation via DHPR or L-type calcium channels opening
Ryanodine receptors release sarcoplasmic reticulum calcium
Crossbridge cycling begins
Relaxation occurs when cytosolic calcium returns to resting levels
Result of SERCA inhibition
Slower contraction
Result of activity on calcium release
Phospholamban is phosphorylated by PKA, can no longer inhibit SERCA, calcium release is quicker
3 key points about the electrogenic NCX
1) Reverse mode (calcium entry) follows depolarisation
2) Forward mode (calcium exit) is promoted by repolarisation
3) Carries one net charge per cycle and contributes to myocyte membrane potential
How do we know that force of contraction varies?
The heart has to pump out all the blood that comes in, but all muscle fibres already contribute to contraction so we can’t recruit more. Therefore the heart must be modulating the rate of activation of the fibres or the contractility of the actin or myosin.
4 ways to modulate force
Increase ventricular stretch
Increase automaticity
Use neurotransmitters to alter rate and calcium handling
Inotropic drugs
Two main ways to change the strength of contraction
Alter calcium transient (amplitude and duration)
Alter myofilament calcium sensitivity
Frank-Starlings Law
Increase in end diastolic ventricular volume increases stroke volume via stretch induced increase in cardiac contractility
Inotropy
Strength of muscular contraction
Chronotropy
Heart rate and rhythm
Lusitropy
Muscular relaxation
6 factors that can increase myofilament calcium sensitivity
Alkalosis Longer sarcomeres Lower catecholamines Decreased ATP Caffeine Lower phosphate
4 important effects of beta-adrenergic stimulation
Decreased myofilament calcium sensitivity
Increased inner calcium
Enhanced sarcoplasmic reticulum calcium-ATPase rate
Altered ryanodine receptor gating
Beta adrenergic agonist mechanism
Stimulate adenylyl cyclase to increase cAMP levels
Activates PKA which phosphorylates phospholamban, decreases troponin I and increases sarcolemma calcium channels
Biphasic response to stretch
Rapid response
Slow force response
Increase in amplitude of calcium transient
Effect of increased rate of AP activation
Less time for calcium extrusion
Decrease in average membrane potential
Decreased overall calcium efflux via NCX
Increased intracellular sodium and calcium
Parasympathetic effects on heart
Decreased SA node discharge rate
Decreased force
Sympathetic effects on heart
Increase SA node discharge rate
Increase calcium influx
Increased sarcoplasmic reticulum pump rate
Decreased sensitivity of troponin for calcium
Regulation of stroke volume and heart rate
Adrenaline and sympathetic activity:
Increases contractility which increases stroke volume which increases CO
Increases heart rate which increases CO
Increased preload also increases stroke volume and therefore CO
3 main force modulation drugs
Cardiotonic steroids
Sympathomimetics
Bypyridines
Cardiotonic steroids
Digoxin
Inhibit sodium pump therefore increase intracellular sodium which reduces calcium extrusion via sodium/calcium pump
Sympathomimetics
Act via beta-1 receptors
Can get desensitised to these
Bypyridines
Act via phosphodiesterase which increases cAMP
Limited use
3 current therapies to reverse the increase in cardiac dimensions
NO - relaxation
Diuretics - decrease blood volume
ACE inhibitors - depress angiotensin axis
Events of the cardiac cycle
Atrial systole Isovolumic contraction Rapid ejection Reduced ejection Isovolumic relaxation Rapid filling Reduced filling
Atrial systole
Atrial depolarisation starts soon after start of P wave
Top up of ventricle by atrial contraction
Can contribute to ventricular filling depending on heart rate
‘a’ wave
Isovolumic contraction
Onset coincides with peak of R wave
Ventricular volume unchanged
Closure of AV valves causes 1st heart sound
‘c’ wave
Rapid ejection
Semilunar valve opens
Rapid increase in aortic flow
Rapid decrease in left ventricle volume
Atrial pressure drops
Reduced ejection
Runoff from aorta to periphery exceeds left ventricular output so aortic pressure drops, but just about left ventricular pressure so ejection is still occurring
Aortic flow drops
Atrial pressure rises
End systolic volume
End systolic volume
Volume of blood left after contraction finishes
About 60 mLs
55 - 75% LV blood has been ejected at this point
Isovolumic relaxation
Beginning of diastole
Aortic valve closes
Produces notch in aortic pressure curve (incisura)
Closing of semilunar valves produces 2nd heart sound
Rapid fall in left ventricular pressure
Aortic pressure remains high
Rapid filling
LA pressure greater than LV pressure causing AV valve to open
Rapid increase in LV volume
3rd heart sound sometimes heard
Slow filling
Diastasis
Equalised pressures
Slow rise in atrial and ventricular pressures
3 positives of ECG
Non-invasive
Fast
Measures cardiac function
Venous pulse wave
Upwards deflections: 'a' = atrial contraction 'c' = ventricular contraction 'v' = venous filling Downwards deflections: 'x' = atrial relaxation 'y' = ventricular filling
Valve openings and closings
Mitral valve closes just before tricuspid
Pulmonary valve opens before aortic
Aortic valve closes before pulmonary
Tricuspid opens before mitral
Right ventricle valves open sooner and close later due to differences in electrical activation and pressures
1st heart sound
AV valve closure at onset of ventricular systole
Low frequency
2nd heart sound
Closure of semilunar valves
Higher frequency but shorter duration
Splitting of second heart sound occurs when pulmonary valve closes after aortic
3rd heart sound
Early diastole
Rapid filling of ventricle causes wall vibrations
Can be heard in healthy children or in ventricular failure
3 reasons a murmur might be heard
Regurgitation
Mitral valve prolapse
Stenosis
LA pressure measurement
Fluid filled catheter with balloon on the end inserted into pulmonary artery
Balloon wedges and blocks channel, stopping flow
Pressure seen is representative of LA
2 measurements of cardiac output
Fick method
- based on conservation of mass
- requires arterial puncture
- indicator dilution using dye
Thermodilution
- indicator dilution technique using cold saline
- measures downstream temperature change instead of dye concentration
Emphysema and vascular resistance
Increases pulmonary vascular resistance
Much of lung tissue destroyed causing high vascular resistance
To maintain flow, RV increases pumping pressure leading to RV hypertrophy and eventually failure
Wolff-Parkinson White Syndrome
Pre-excitation syndrome where ventricles are electrically activated earlier than normal
Accessory pathway is abnormal connection between atria and ventricles which does not have delaying properties of AV node
ECG properties of WPW
Normal sinus rhythm
Shortened PR interval
Wide QRS complex
Delta wave
Symptoms of WPW
Ventricular tachyarrhythmia
Syncope
Palpitations
Small risk of sudden death
Treatment of WPW
Drugs to control fast rhythms
Ablation of accessory pathway
Long QT syndrome
Abnormally long delay between depolarisation and repolarisation of ventricles
Drug-induced or genetic
Drug induced LQTS
Anti-arrhythmics
Antihistamines
Potassium channel blockers
Genetic LQTS
Mutation in gene for ion channels prolongs duration of ventricular action potential which lengthens the QT interval
Hyperkalaemia ECG
Tall, peaked T waves due to faster repolarisation
Hypokalaemia ECG
Flat T waves due to slower depolarisation
Ventricular and atrial hypertrophy ECG
Bigger waves on all leads
Hypercalcaemia ECG
Shortened QT interval due to reduced action potential duration
Hypocalcaemia ECG
Lengthened QT interval due to increased action potential duration
Digitalis ECG
ST segment depression
T wave inversion
PR interval prolongation
Sequence of changes of Q-wave infarction
Tall peaked T waves ST segment elevation Reduced R wave amplitude T wave inversion Pathological Q waves ST segment returns to normal T waves often return to normal (within weeks)
T wave changes in MI
Tall and peaked Earliest sign Localised to leads facing areas of injury 5-30 minutes after onset Later, symmetrically inverted
ST segment changes in MI
Elevation often earliest observed sign
Seen in leads facing infarcted area
Often followed by definitive QRS changes
May return to normal
QRS changes in MI
Low R wave voltages and pathological Q waves in local area
Wavefronts coming toward electrode reduced or absent
Wavefronts moving away from electrode emphasised
Reciprocal changes in MI
In leads opposite those facing the infarct, ST segment depression and tall T waves
Preload
Degree of filling
Stretch of muscle just before contraction
Afterload
Pressure against which the ventricle contracts
Four determinants of ventricular performance
Preload
Afterload
Inotropic state
Heart rate
Inotropic state
Intrinsic ability of myocardium to contract with given preload and afterload
Chronotropic state
Heart rate
Increased HR = increased CO but decreased SV
Factors that affect preload
Blood volume Venous tone Posture Heart rate Atrial contraction Intrathoracic pressure Ventricular compliance
Factors that affect afterload
Systemic pressure
Vasoconstriction
Aortic stenosis
Ventricular stress
Factors that affect inotropic state
ANS Catecholamines Force-frequency relation Action potential changes Cardiomyopathy Inotropic drugs
Factors that affect heart rate
ANS
Catecholamines
Ejection fraction
(EDV - ESV) / EDV
x 100
Normal ejection fraction
55-60% at rest
85% during exercise
<50% = depressed contractility
Stroke work
about MAP x SV
