CVR week 2 Flashcards
What are the 4 main components of the myocardium?
contractile tissue
connective tissue
fibrous frame
specialsied conductive system
What are cardiac myocytes?
contractile myocytes of the cardiac muscle
What is Excitation-contraction coupling
The process of converting an electrical stimulus (action potential) to a mechanical response (muscle contraction). It begins when the action potential depolarizes the cell and ends when ionized calcium (Ca2+) that appears within the cytosol binds to the Ca2+ receptor of the contractile apparatus.
describe the process of excitation contraction coupling?
The action potential travels down the T-tubules depolarising the cell membrane and also depolarises sarcomeres resulting in an influx of calcium ions into the sarcoplasm.
Cardiac muscle contraction occurs via the sliding filament model of contraction, What is the sliding filamnet model of contraction?
It then binds to cardiac troponin-C which moves the tropomyosin away from the actin-binding site thus exposing it and initiating cross-bridge binding.
The heart relaxes when ion exchangers and pumps transport Ca2+ uphill, out of the cytoplasm.
Once calcium is bound to troponin-C and the conformational change of tropomyosin has occurred, myosin heads can bind to actin.
Following this ADP and inorganic phosphate are released from the myosin head so the power stroke can occur. In this the myosin head pivots and bends, pulling on the actin and moving it, causing muscle contraction.
After this occurs a new molecule of ATP binds to the myosin head, causing it to detach from the actin. Finally, the ATP is hydrolysed into ADP and inorganic phosphate. Following this, the cycle can begin again and further contraction can occur.
The heart relaxes when ion exchangers and pumps transport Ca2+ uphill, out of the cytoplasm.
features of the myocardial cell
- filled with cross-striated myofibrils
- many mitochondria
- plasma membrane regulate excitation-contraction couply and relaxation
- plasma membrane seperate cytosol from extra-cellular space and sarcoplasmic reticulum
myocardial metabolism:
Relies on free fatty acids during aerobic metabolism (efficient energy production).
During hypoxia, there is no FFA metabolism, thus anaerobic metabolism ensues. This relied on metabolising glucose (anaerobically) producing energy sufficient to maintain the survival of the affected muscle without contraction.
Ultrastructure of myocardial cells:
Contractile proteins are arranged in a regular array of thick and thin filaments (The so called Myofibrils).
A-band: the region of the sarcomere occupied by the thick filaments.
I-band: is occupied only by thin filaments that extend toward the centre of the sarcomere from the Z-lines. It also contains tropomyosin and the troponins.
Z lines bisect each I-band.
what is a sarcomere?
The sarcomere: the functional unit of the contractile apparatus,
The sarcomere is defined as the region between a pair of Z-lines,
The sarcomere contains two half I-bands and one A-band.
what is the sarcoplasmic reticulum? what is the sarcolemma?
The sarcoplasmic reticulum is a membrane network that surrounds the contractile proteins,
The sarcoplasmic reticulum consists of the sarcotubular network at the centre of the sarcomere and the subsarcolemmal cisternae (which abut the T-tubules and the sarcolemma).
The transverse tubular system (T-tubule) is lined by a membrane that is continuous with the sarcolemma, so that the lumen of the T-tubules carries the extracellular space toward the center of the myocardial cell.
Contraction of sarcomere:
Sliding of actin over myosin by ATP hydrolysis through the action of ATPase in the head of the myosin molecule.
These heads form the crossbridges that interact with actin, after linkage between calcium and TnC, and deactivation of tropomyosin and TnI.
myosin
2 heavy chains- also responsible for heads
4 light chains
heads are perpindicular at rest, bend towards centre during contraction
actin
globular proetin
double stranded helix
both form the F actin
tropomyosin
Elongated molecule, made of two helical peptide chains.
It occupies each of the longitudinal grooves between the two actin strands.
Regulates the interaction between the other three!
troponin- 3 types
Types of troponin:
I: with tropomyosin inhibit actin and myosin interaction.
T: binds troponin complex to tropomyosin.
C: high affinity calcium binding sites, signalling contraction.
The latter bond, drives TnI away from Actin, allowing its interaction with myosin
titin
titin molecules anchors myosin to Z-line
sumamry of muscle contraction:
1- Ca++ enter the cell through Ca++ channels on sarcolemma during depolarization(phase 2) and triggers release of Ca++ by terminal cisternae. =(Ca++ induced Ca++ release)
2- Ca++ binds to troponin-C inducing a conformational change in the troponin complex. (Ca+ binds to troponin, so troponin releases actin. The free actin can now bind to myosin.)
3- Myosin heads bind to actin, leading to cross-bridge movement(=sliding) (requires ATP hydrolysis) and reduction in sarcomere length. (muscle contraction)
4- Ca++ is re-sequestered(Ca++ reuptake) by sarcoplasmic reticulum by sarco- endoplasmic reticulum calcium ATPase (SERCA) pump.
5- Ca++ is removed from troponin-C and myosin unbinds from actin (requires ATP hydrolysis); this allows the sarcomere to resume its original, relaxed length. (muscle relaxation)
40 degree angle
projections on the myosin filament
Cardiac Cycle Phases:
LV contraction:
LV relaxation:
Ventricular Contraction- systole
Wave of depolarisation arrives,
Opens the L-calcium tubule, {ECG: Peak of R},
Ca2+ arrive at the contractile proteins,
Left ventricular pressure rises > Left artrial pressure:
Mitral Valve closes: M1 of the 1st Heart Sound,
Left ventricle pressure rises (isovolumic contraction) > aorta pressure
aortic valve opens and Ejection starts.
Ventricular Relaxation
Left venticular pressure peaks then decreases.
Influence of phosphorylated phospholambdan, cytosolic calcium is taken up into the SR.
“phase of reduced ejection”.
Aortic flow is maintained by aortic distensibility.
Left Ventricular pressure < Aotic pressure, Aotic valve closes, A2 of the 2nd Heart Sound, “isovolumic relaxation”- period of time between Aortic vakve sutting and mitral valve opening, then Mitral Valve opens
Ventricular Filling
Left Ventricular pressure < Left Atrium pressure, MV opens, Rapid (Early-phase) filling starts - passive
Ventricular suction (active diastolic relaxation), may also contribute to E filling, S3 sound
Diastasis (separation): LVentricular pressure = LAtrium pressure, filling temporarily stops. net flow is 0
Filling is renewed when Atrial contraction (augmentation), raises L Atrial pressure creating a pressure gradient. sometimes hear S4 sound- always pathological
(older people are more reliant on atrial augmentation, rely on it for roughly 40% of blood movement)
mitral valve shuts- 1st heart sound (Lub)
Physiologic vs. Cardiologic systole
Physiological:
1. Isovolumic contraction,
2. Maximal ejection
Cardiological:
1. From M1 to A2,
2. Only part of isovolumic contraction (includes maximal and reduced ejection phases)
preload and afterload
Preload: is the load present before LV contraction has started.
Afterload: is the load after the ventricle starts to contract.
starlings law:
the larger the volume of the heart, the greater the energy of its contraction and the amount of chemical change at each contraction. This eventually reaches a plateau
how do you calculate left ventricular pressure?
LV filling pressure: is the difference between LAp and LV diastolic pressure.
starlings law relavence to heart failure:
define contractility and elasticity:
Contractility (inotropic state): the state of the heart which enables it to increase its contraction velocity, to achieve higher pressure, when contractility is increased (independent of load)
Elasticity, is the myocardial ability to recover its normal shape after removal of systolic stress.
compliance and diastolic distensibility definitions
Compliance is the relationship between the change in stress and the resultant strain.(dP/dV).
Diastolic distensibility is the pressure required to fill the ventricle to the same diastolic volume.
Embryology of the heart:
what is gastrulation? name of layers?
mass movement and invagination of the blastula to form 3 layers- ectoderm, mesoderm and endoderm
what develops from the ectoderm?
Ectoderm – (outside) – skin, nervous system, neural crest (which contributes to cardiac outflow, coronary arteries)
what develops from mesoderm?
middle – all types of muscle, most system, kidneys, blood, bone
(some cells can ‘forget’ what theyre supposed to e.g. muscle in artery walls turning to bone)
what develops from endoderm?
gastrointestinal tract (inc liver, pancreas, but not smooth muscle), endocrine organs
the heart fields: what will they develop to?
FHF - (first heart field) future left ventricle, genrates sacoffold which is added to by second heart field
SHF- (second heart field) outflow tract, future right ventricle, atria
example of cardiac transcription factors?
Nkx2.5
GATA
Hand
Tbx
MEF2
Pitx2
Fog-1
transcription factors are expressed in a tissue specific manner
3 stages of cardiac formation:
formation of primitive heart tube
cardiac looping
cardiac seperation
formation of primative heart tube? how? what will it look like?
3rd week:
horseshoe shape region (called cardiogenic region) of FHF and SHF, 2 endocardial tubes form and then fuse to form a single primative heart tube
Primative heart:
top is bulbis cordis (foremsmost right ventricle and part of outflow tracts), then primative ventricle, then primative atria
cardiac looping?
bulbis cordis moves inferiorly, anteriorly to the embryos right,
primative ventricle moves to embryos left side
primitive atrium and sinus venosus move superiorly and posteriorly
cardiac septation- what does heart look like before? what occurs in cardiac septation?
currently blood flows into one common atria and one common ventricle connected by atrioventricular canal and then out of truncus arteriosus, mases of tissue called endocardial cushions grow from sides of atrioventricular canal to make 2 seperate openings called R and L atrioventricular canals
embryology of blood circulation-
Blood islands form in the extraembryonic mesorderm (they are cores of hemoblasts surrounded by endothelial cells) these blood cells then vascularise the yolk sac, chorionic villus and stalk
vasculogenesis commences
Angioblasts (from splanchnopleuric mesoderm) coalesce to form angioblastic cords throughout embryonic disc
what is angiogenesis?
driven by angiogenic growth factors and takes place via proliferation and sprouting (growing of blood vessels)
Other mesodermal cells are then recruited to make walls
what happens to 3rd aortic arches?
Portion between 3rd and 4th aorta disappears
Become common carotid arteries, and proximal internal carotid arteries
Distal internal carotids come from extension of dorsal aortae
what happens to 1st and 2nd aortic arches?
1st – small part of maxillary (blood to jaw)
2nd - artery to stapedius (inner ear)
what happens to right dorsal aorta and right 4th aortic arch arches?
R dorsal aorta looses connections with midline aorta and 6th arch, remaining connected to R 4th arch
Acquires branch 7th cervical intersegmental artery, which grows into R upper limb
Right subclavian artery is derived from right 4th arch, right dorsal aorta, and right 7th intersegmental artery
what happens to left dorsal aorta and left 4th aortic arch arches?
Left dorsal aorta continues into trunk
Left 7th cervical intersegmental artery, which grows into left subclavian artery
Right subclavian artery is derived from right 4th arch, right dorsal aorta, and right 7th intersegmental artery
what happens to 5th aortic arches?
there are none
what happens to 6th aortic arches?
Right arch may form part of pulmonary trunk
Left arch forms ductus arteriosus – communication between pulmonary artery and aorta
how does the heart develop on the left side embryonically?
the node secretes a protein that circulate to left due to left knocking by cillia - gradient in left switches of differnet transition fcators to transduce looping
name the three types of capilalries? and where they’re most common? how is flow regulated in all types?
Three types of capillary: continuous (most common), fenestrated (kidney, small intestine, endocrine glands), discontinuous (liver sinusoids)
flow regulated by precapillary sphincters
What drives embryonic vessel development?
- Angiogenic growth factors, vascular endothelial growth factor, angiopoietin 1 & 2
- Repulsive signals – Plexin / semaphorin signalling, ephrin / Eph interactions
- Attractive signals
Name the 4 major blood groups?
A, B, AB, O (also bombay group- very rare)
ABO typing- how is blood group inherited? what do genes transcribe for?
ABO antigens inherited in mendelian pattern and the enzymes that make the antigens are coded for by 2 genes on Chromosome 9. This causes codominance.
ABO antigen production after enzyme production- what happens?
For H antigen there is not modification
For A antigen enzyme produced attaches a sugar
For B antigen enzyme produced attches a different sugar
For bombay- full H antigen isn’t present
ABO Antibodies- when does body begin producing these? when is conecentration highest? what happens after that? what are ABO antibodies?
doesn’t require prior exposure of antigen to produce antibody
Infants <3 months produce few if any antibodies (dependant on maternal antibodies prior to this)
Maximal concentraion of antobodies is reached by 5-10 years old and the amount then decreases with age.
Mix of IgG and IgM (mainly for group A and B)
Antibodies in plasma and antigens on erythrocyte surface present in blood groups? Gorup AB (universal recipient)- No antibodies, Antigen A and B
Group O (universal donor)- antibody A dnd B, no antigens
Group A- Antibody B, antigen A
Group B- Antibody A, antigen B
Gorup AB (universal recipient)- No antibodies, Antigen A and B
Group O (universal donor)- antibody A dnd B, no antigens
rhesis D antigen:
over 45 different types
Rh D coded for by 2 genes on 1st chromosome
does require prior exposure of antigen to produce antibody
what is HDFN? how can it be prevented?
Can cause haemolytic transfusion reactions and haemolytic disease of the fetus and newborn (HDFN)
red blood cell, platelet, and plasma transfusions.
Prevented by given antiD prophalaxis
Difference between forwards and reverse typing? what is being tested for in each? what will a postive test look like?
both used in every patient
In forwards typing:
patients rbc mixed with serum with known anti A or anti B
or RhD antibodies.
(testing for the antigens)
In reverse typing:
patients plasma is mixed with rbc of known type
(testing for antibodies)
agglutination- positive, line forms at top of gel
what is the indirect antiglobulin test?
crossmatch- repeat typing tests with donor blood to be sure
mix recipients serum with donor wbc to check if reaction (same as forwards typing)
what is direct antiglobulin test?
only done if transfussion reaction has occured to figure out whats happend
who can donate blood?
17-65 yrs old for 1st time donors
50-158kg
questionnaire screened- disease, health, lifestyle, travel, medical history,
who are exempt from dontaing blood?
temporary- travel, tatoos/peircings, pregnant and 6 months after
Permanent:
certain disease, hiv positive, hep B+C, recieved blood transfusion or products since 1980
what can you donate?
whole blood
aphresis- part, blood removed and externally seperated, bit wanted removed, rest returned
Tests done post-donation?
All:
Hep B,C,E ,HIV, Syphylis, HTLV, groups and antibodies
Some:
CMV, Malaria, West Nile Virus,
How is blood stored and processed after donation?
first small bag taken- tested
larger bag- centrifuged, plasma only kept from males (female plasma more antigenic so more trabnsfussion reactions)
then frozen (Fresh Frozen Plasma) or processed to crypoprecipotate
rbc- leocodepletion to remove wbc particularly T cells as they can lead to
graft vs host disease
How are erythrocyted stored?
Stored at 4oC, shelf life 35 days
Some units irradiated to eliminate risk of transfusion e.g. in imunocompromised person increased associated graft vs host disease
when would someone be given a erythrocyted transfussion?
Indications for erythrocyte transfusion:
Severe anaemia (not purely iron deficiency)
Transfusion threshold:
Haemoglobin <70 g/L or <80 g/L + symptoms
Transfuse 1 unit and recheck full blood count
How are platelets produced and stored?
Most units pooled from 4 donations
Some single-donor apheresis units
Stored at 22oC with constant agitation, 7 day shelf life
when would someone be given a platelet transfussion?
Indications of need:
Thrombocytopaenia (low platelet count) and bleeding
Severe thrombocytopaenia < 10 x 10^9 due to marrow failure (normal is 150-450 x 10^9)
Plasma transfusion? where is plasma from?
Only men:
fresh frozen plasma-
From whole donations or apheresis
Patients born > 1996 can only receive plasma from low vCJD risk (not UK plasma)- rule is relaxing
Pooled donations can be more standardized amounts of clotting factors
When is someone given plasma donation?
Indications
Multiple clotting factor deficiencies and bleeding (DIC)
Some single clotting factor deficiencies where no clotting factor substitute available
what is cryoprecipitate? When is it used? what is dose?
Made by thawing FFP to 4oC and skimming off fibrinogen rich layer
Used in DIC with bleeding, and in massive transfusion
Therapeutic dose: 2 packs (each pooled from 5 plasma donations)
Immunoglobulins - where from? when normal immunoglobulins used and when specific are used?
Made from large pools of donor plasma (higher risk), more commonly made from recombinant DNA now
Normal IVIg:
Contains Ab to viruses common in population
Used to treat immune conditions
Specific IVIg:
From selected patients
Known high AB levels to particular infections/conditions
- Anti D immunoglobulin used in pregnancy
- VZV immunoglobulin in severe infection- chicken pox and shingles
granuolocytes- when and how often used?
Used very rarely
Effectiveness unknown
factor concentrates/clotting factors transfusion
Single factor concentrates:
Factor VIII for severe haemophilia A,
Fibrinogen concentrate (Factor I)
Prothrombin complex concentrate (Beriplex/Octaplex):
Multiple factors
Rapid reversal of warfarin (blood thinner)
What measure put in place to enable safe delivery of blood transfusions?
- correct identification (2 sample rule,
Hand-written patient details, cross matched)
what are some of the way we can avoid transfusion?
Ensure optimise patients with planned surgical procedures pre-op
Use of EPO-stimulating drugs
In renal failure and In patients with cancers
Intraoperative cell salvage (give their blood back to them)
IV iron for severe iron deficiency
Some patients may tolerate lower haemoglobin concentrations and not require transfusion at all
If ABO is incompatible pateint may have haemolytic reaction- what are symptoms?
release of cytokines causing acute renal failure and fall in blood pressure causing shock
DIC (deseminated intravascular coagulation) - uncontrolled clotting
Can be fatal
If transfusion has bacterial infection what symptoms could cause for patient?
fever and chills, hypotension, shock
(most common with platelets)
What is TRALI? what are the symptoms?
Transfusion related lung injury, antibody in donors blood reacts with epithelium in lungs causing inflamation and pulmonary oedema
symptoms:
shortness of breath, cough and froffy sputum, hypotension and fevers
What is TACO?
Transfussion- associated circulatory overload
overload of fluid can put person intop heart failure
phases of build up of atherothrombosis
normal
fatty streak
fibrous streak
atherosclerosis-sclerotic plaque
plaque Rupture/fissure & thrombosis
myocardial infarction
ischaemic stroke
critical leg ischamia
cardiovascular death
activation - shape change of platelets? why does it do this?
Activation - Shape change
Smooth discoid changes to spiculated (spiky) + pseudopodia
Increases surface area
Increases possibility of cell-cell interactions
Glycoprotein IIb/IIIa (GPIIb/IIIa) receptor- also known as? what does it do once activated?
also known as integrin aIIbb3, sit on surface of resting platelet and once activated allows crosslinking between adjacent platelets
once activated:
Increases number of receptors
Increases affinity of receptor for fibrinogen
Fibrinogen links receptors, binding platelets together (platelet aggregation)
platelet receptor- what happens after atherosclerotic plaque rupture?
Platelets bind to damaged vessel wall:
-Collagen receptors bind to subendothelial collagen which is exposed by endothelial damage
-GPIIb/IIIa also binds to von Willebrand factor (VWF) which is attached to collagen
Soluble agonists are also released and activate platelets
aspirin- how does it act as an antiplatelet drug? at a low dose vs at high dose what does it inhibit?
inhibits thormboxane A2 (which acts on TPa to allow platelet activation)
low dose inhibits COX1 in platelets
high dose inhibits COX-1 and COX2 in endothelial cells - act as anti-platelets (prostacyclin not produced)
P2Y1 Receptor- what proetin is it coupled with? what does it inhibit and promote? what does it do for platelet?
G protein coupled receptor: Gq protein
P2Y1: promotes production of phospholipase C into protein kinase C and Ca.
This enables the initial aggregation and shape change, GPIIb/IIIa fibrinogen cross-linking
P2Y12 Receptor- what proetin is it coupled with? what does it inhibit and promote? what does it do for platelet?
G protein coupled receptor: Gi protein
P2Y12: promotes PI3 Kinase but inhibits adenylate cyclase which prevents cAMP being produced.
Amplification of platelet activation, aggregation and granule release
How does ADP play a role in platelet activation? where does ADP come from?
ADP (produced by dense granule in platelet) activates P2Y12 and P2Y1
What receptor does thrombin act on?
Thrombin activates PAR-1 and PAR-4 (protease-activated receptors) leading to platelet activation and release of ADP
How does thrombin activate PAR-1?
aminophospholipds only on inner side (by transolcase filling them)
activated platelets release Ca from intracellular stores
Ca then inhibits translocase, but activates scramblase (scrambles aminiophospholipids)
Va and Xa are attracted to these aminophospholipids, which allows assembly of prothrombinase complex and generation of thrombin (which then activates platelet activation pathway and is used in coagulation cascade)
Fibrinolytic system? promoted by, inhibited by?
endothelium release tPA (tissue plasminogen activator) which cleaves plaminogen forming plasmin, plasmin breaks down fibrin into fibrin degradation products
The cleaving of plasminogen is inhibited by PAI-1 (plasminogen activator inhibitor-1), cleaving of plasminogen to fibrogen is inhibited by antiplasmin
what do alpha granules do?
store and release coagulation factors e.g fibrinogen etc.
release inflammatory mediators attracting leucocytes
The PSGL-1 molecules on surface of leucocytes allow adhesion with platelets allowing for further release of alpha granules
