Cardiovascular System Flashcards
What is haemopoiesis?
Formation of the blood cells
What is the lifespan of a red blood cell?
120 days
What is the lifespan of a platelet?
7-10 days
Where do the precursors of mature blood cells derive from?
Bone marrow.
In utero; yolk sac, liver and spleen, bone marrow
Children - all bones
Adults - axial skeleton
Haemopoietic stem cells
They are pluripotent, so they replicate and differentiate into red cells, white cells, platelets and marrow stroma.
Control of haemopoiesis
Replication and differentiation is stimulated by hormonal growth factors.
For red blood cells, the hormone is erythropoietin (EPO) which is used for renal failure therapy. White blood cells the hormone is Granulocyte-macrophage colony-stimulating factor (GM-CSF) used in chemotherapy. For platelets its thrombopoietin (TPO) drives production of platelets used in people who have low platelet count.
Histological features of red blood cells (erythrocytes)
Simple anucleate cells with no mitochondria
Biconcave
7.5micrometer diameter
Contain haemoglobin glycolysis enzymes
Haemoglobin
Carries oxygen from the lungs to the tissue. 4 globin chains each with its own haem group (O2 carrier)
Tetrametric protein with 2 alpha and 2 beta chains.
Allows O2 to reversibly combine with Fe2+ ions in an aqueous environment.
Method of looking at haemoglobin: High performance liquid chromatography (HPLC)
Separates haemoglobin on basis of electrical charge
Method of looking at looking at haemoglobin: Electrophoresis
Separates haemoglobin on basis of electrical charge
Acid and alkaline conditions
Abnormalities of haemoglobin
Sickle cell disease (heterozygous dominant)
Lack of the gene for alpha/beta thalaessemia - beta is more common since this is the chain that changes from the baby form of Hb.
What is the name for the condition where there is a deficiency of Hb?
Anaemia
For men and women respectively, what are low levels of Hb? Why do women have lower levels of haemoglobin?
Men - <130g/L
Women - <110g/L
Women have lower levels due to menstrual bleeding
What is acute blood loss?
Blood loss results in loss of red blood cells and plasma.
Initially the haemoglobin levels will be unchanged.
Whart is a result of production failure of RBC?
Hypoplastic anaemia (not enough) Dyshaemopoeitic anaemia (ineffective production)
Why could there be increased removal of RBC?
Blood loss or haemolytic loss (breakdown of RBC). This can be due to intrinsic (within RBC) abnormalities or extrinsic (outside RBC) abnormalities.
Aplastic anaemia
Can be inherited or acquired for reasons such as idiopathic, chemical/drug, viral, radiation.
Dyshaemopoietic anaemia
Multiple mechanisms e.g. anaemia of chronic disease
Defective haemoglobin synthesis.
Defective DNA synthesis.
Haemolytic anaemia can be due to 2 reasons
Intrinsic RBC abnormalities
Extrinsic abnormalities
Haemolytic anaemia + intrinsic RBC abnormalities
It can be acquired such as with PNH (haemolysis - breaking apart of RBCs) or it can be for hereditary reasons such as membrane disorders, enzyme disorders, and haemoglobin disorders.
Haemolytic anaemia + extrinsic RBC abnormalities
Antibody mediated (AIHA) Mechanical trauma (DIC) Infections (Malaria) Chemicals (lead poisioning) Sequestration (hypersplenism)
Iron deficency anaemia
This is the most common cause of anaemia caused by chronic bleeding in the gastrointestinal tract, poor diet, malabsorption, hook worm.
There is a reduction in mean amount of Hb in cell and cell volume.
Types of white blood cell
Neutrophils Monocytes Lymphocytes Basophils Eosinophils
All cells except lymphocytes are termed phagocytes.
What is the most abundant WBC?
Neutrophils
What do neutrophils do?
They phagocytose bacteria and foreign material by releasing chemotaxins and cytokines important in the inflammatory response.
What is the inflammatory response?
Increased temperature
Increased blood flow
Local pain
What happens when there is a decreased number of neutrophils?
Recurrent bacterial infections
Monocytes
Macrophages which also phagocytose bacteria+foreign material. The majority transit through the blood to the tissues. They are dendritic cells which present antigens to the immune system.
How do neutrophils and monocytes differ?
Monocytes are present in tissues.
What do basophils become?
Basophils migrate to tissues becoming mast cells.
What are mast cells?
Mast cells are filled with histamine containing granules and express surface IgE. They have an important role in the immune and allergic response.
Eoisinophils
Rare
Special role in protection against parasites.
Where do B-lymphocytes mature?
Bone marrow of the rib
What percentage of lymphocytes in the blood do B-lymphocytes make up?
20%
Role of B-lymphocytea
Generate antibodies when stimulated by foreign antigens in the humoral immunity response.
Where do T-lymphocytes matures?
Thymus
What percentage of lymphocytes in the blood do T-lymphocytes make up?
80%
B-lymph have ??? receptors
T lymph have ??? receptors
B - IgE
T - TCR
Two types of T-lymph.?
Cytotoxic T-cells which target infected cells for death (cell mediated immunity).
T-helper cells stimulate the immune response of B-lymphocytes.
How does blood inside the vessels remain fluid?
Endothelial cells, anticoagulant pathway and fibrinolytic pathway actively keep it fluid. Platelets and proteins of the coagulation cascade circulate in an inactive state.
What is thrombosis?
When blood clots inside the vessel instead of outside the vessel as it should.
What do platelets contain?
Electron dense granules containing calcium, ADP/ATP and serotonin.
Alpha granules containing platelet derived growth factor (PDGF), fibrinogen, heparin antagonist (PF4) and VWF (von Willebrand Factor).
Platelets + primary haemostasis.
Platelets circulate in an inactive state. When there is damage to the blood vessel, they adhere to collagen via glycoprotein Ia on sub-endothelium.
Glycoprotein Ib and Glycoprotein IIIa bind von Willebrand Factor. Binding causes platelets to change shape and activate become elongated. Tethering of platelets causes them to activate further receptors on their surface which enables further crosslinking
Platelets + primary haemostasis.
Platelets circulate in an inactive state. When there is damage to the blood vessel, they adhere to collagen via glycoprotein Ia on sub-endothelium.
Glycoprotein Ib and Glycoprotein IIIa bind von Willebrand Factor. Binding causes platelets to change shape and activate become elongated. Tethering of platelets causes them to activate further receptors on their surface which enables further crosslinking with VWF and fibrinogen.
Activation releases contents and results in intracellular signalling causing platelets to release their stored granular contents. Aggregate to form a platelet thrombus (haemostatic plug). Lack of function leads to bleeding. Change in number leads to bleeding/thrombosis.
Platelet bleeding disorders: Bernard-Soulier syndrome
Cause and impacts?
Deficiency of GPIb receptor
Affects platelet adhesion
Platelet bleeding disorders: Glanzmann’s thrombasthenia
Cause and impacts?
Defect of GPIIb/IIIa receptor
Affects platelet cross-linking and aggregation.
Platelet bleeding disorders: Hemansky-Pudlak
Cause and impacts?
Defect in dense storage granules
Affects Platelet activation and aggregation
When is there a reduction in platelet number?
Thrombocytopenia
Increased bleeding
Spontaneous bleeding
When is there a increase in platelet number
Thrombocytosis
Arterial thrombosis
Venous thrombosis
Plasma
Clear, straw coloured liquid left after cellular component of blood is removed. It is 90% water but also has salts, glucose and proteins.
Proteins in plasma
Albumin
Carrier proteins
Coagulation proteins
Immunoglobulins
Where is albumin produced?
The liver
What is the function of albumin?
To determine oncotic pressure of the blood and keep intravascular fluid in that space and keep the pressure within vessel.
What can a lack of albumin lead to?
Oedema
seen in liver disease; nephrotic syndrome
What produces immunoglobulins?
B-lymphocytes
What are immunoglobulins?
Antibodies
Different classes of immunoglobulins?
IgG IgA IgM IgE IgD
What is the Coagulation Cascade?
Series of enzymes that circulate in an inactive state. They are sequentially activated in a ‘cascade sequence’ and convert soluble fibrinogen into insoluble fibrin polymer. This generates a stable clot.
What does inhibition of fibrin production lead to?
Bleeding
A sign of failure of coagulation proteins
Bleeding
A sign of overactive coagulation proteins
Thrombosis
What drugs affect platelet function? When are they used?
Aspirin
Clopidogrel
Used following a heart attack to reduce risk of further clots
Hemophilia A symptom
severe bleeding into muscles and joins
Why does Hemophilia A take place?
Deficiency of factor VIII, a blood clotting protein
How is Hemophilia A treated?
Recombinant factor VIII
Hemophilia A + genetics
X-linked condition
Alternate generations
Hemophilia B
Severe bleeding into muscles and joints
Why does Haemophilia B take place?
Deficiency of factor IX
How is Hemophilia B treated?
Recombinant factor IX
Von Willebrand Disease
Usually mild bleeding disorder which is often unrecognised due to a deficiency in VWF
Affect of aspirin and clopidogrel on bleeding?
Affect platelet function by reducing it
Affect of chemotherapy on bleeding?
Reduces platelet numbers
Which drugs affect coagulation cascade?
Heparin - a natural anti-coagulant produced by basophils and mast cells which inhibits platelet function while inactivating various coaguation factors such as factor IX
Warfarin
oral anticoagulants
Affect of steroids on bleeding?
Steroids affect tissues making them weaker causing bruising and bleeding
Liver disease + Blood
Coagulation factors such as factor VIII and factor IX are synthesised in the liver so LD is often associated with bruising and bleeding and prolonged prothrombin time.
May also result in low platelets.
Vitamin K + blood
Necessary for functional activity of coagulation factors II, VII, IX and X. Warfarin interferes with the vitamin K activation pathway.
Manifests as prolonged prothrombin
Disseminated intravascular coagulation
Breakdown of haemostatic balance.
Simultaneous bleeding and microvascular thrombosis which is life threatening.
Can cause sepsis
Transfusion reactions
If the patient is transfused with red blood cells that have antigens on their cell surface which the patient lacks on their own RBCs, the new RBCs are seen as foreign and they are haemolysed.
Blood group A alleles and plasma antibodies
AA or AO
Anti-B antibodies
Blood group B alleles and plasma antibodies
BB or BO
Anti-A antibodies
Blood group AB alleles and plasma antibodies
AB
No antibodies
Blood group O alleles and plasma antibodies
OO
Anti-A and Anti-B antibodies
Other blood group
Rhesus system (Rh)
5 most important antigens in the Rhesus system
D C c E e
Which is the most clinically significant antigen in the Rhesus system?
D
Responsible for the most clinical issues associated with the system
Can either be present Rh D+ or absent Rh D-
Anti-D and pregnancy
If women who are Rh D antingen negative (dd) have a baby inside which has Dd genotype, and D-antigen negative mother is exposed to D antigen from baby’s red blood cells, immunoglobins called IgG anti-D produced by the mother. As a result, baby causes transfusion reaction against mum. The IgG Anti-D can cross placenta and haemolyse the baby’s red cells.
What are packed red cells?
Packed = plasma depleted
When are platelets administered medically?
On oncology wards to patients who have bone marrow failure.
What is HAS?
Human albumin solution
Physiological plasma expender
Used to increased oncotic pressure (liver disease, nephrotic syndrome) keeping fluid within vessels.
Can reduce oedema.
What is gastrulation?
Mass movement and invagination of the blastula to form 3 layers:
- ectoderm
- mesoderm
- endoderm
What does the ectoderm eventually become?
Outside skin
Nervous system
Neural crest (which contributes to cardiac outflow and coronary arteries)
What does the mesoderm eventually become?
All types of muscle
Most systems
Kidneys
Blood
What does endoderm eventually become?
Gastrointestinal tract (including liver and pancreas, but not smooth muscle) Endocrine organs
What does FHF stand for? What will it eventually become?
First heart field (future left ventricle)
The FHF generates a scaffold which is added by the second heart field and cardiac neural crest.
What does SHF stand for? What will it eventually become?
Second heart field (future outflow tract, future right ventricle, future atria)
During which days does the primitive heart tube form?
18-22
Why does the primitive heart tube begin to form?
Diffusion alone is no longer capable of sustaining the embryo
Where do progenitor heart cells originate from?
The epiblast
What happens on day 16?
Progenitor heart cells migrate through steak to the splanchic layer of lateral plate mesodemr. Cells specialise from lateral to medial to become different parts of the heart.
Where does the secondary heart field reside?
Splanchic mesoderm ventral to the pharynx. Cells extend laterally to form the left and right outflow.
What happens when the primary heart field cells are established?
They are induced by the pharyngeal endoderm to form cardiac myoblasts ad blood islands that develop into blood cells and vessels via vasculogenesis.
What happens from the blood islands
Blood islands unite into a horse-shoe endothelia lined tube surrounded by myoblasts. This is called the CARDIOGENIC region. The intraembryolic cavity (primitive body) surrounding it develops into the PERICARDIAL CAVITY.
The bilateral and parallel blood islands develop to form dorsal aorta (pair of longitudinal vessels).
What happens as the embryo folds head to toe and laterally (coupled with the rapid growth of the brain)
The heart and pericardial cavity move first to the cervical region and then to the thorax.
What happens to the developing heart tube after this
poles
The developing heart tube receives venous drainage as its caudal pole and begins to pump blood out of the first aortic arch into the dorsal aorta at its cranial pole. It bulges more into the pericardial cavity.
What happens on day 22?
The heart begins to beat
What happens on day 23?
Heart tube lengthenes and begins to bend
As looping of the heart tube begins, what begins to appear?
Primordial structures.
The atrial portion (paired suture outside the pericardial cavity) forms a common atrium and is incorporated into the pericardial cavity.
The atriventricular junction remains narrow and forms the atrioventricular canal which connects the common atrium and the early ventricle.
What does the ‘bulbis cordis’ develop into?
The trabeculated part of the right ventricle.
What does the conus cordis (the mid-portion of the bulbus cordis) develop into?
The outflow tracts of the ventricles
Before cardiac separation, what is there?
one common atrium and one common ventricle
Process of cardiac separation
The cardiac septum forms and the septum primum extends from the endocardial cushions into the atria from the atrioventricular canal. The ostium primum (the opening between the septum and endocardial cushions) closes as the endocardial cushions extend whilst perforations appear in the upper end of the septum primum forming the ostium secondum, eventually being closed by overlap by the septum secondum. Septum secondum extends to form the superior atrial wall, where the foramen ovale is found. At birth, as the lungs become functional the left atrial pressure exceeds that of the right forcing the septum primum against the septum secondum. This forms the fossa ovalis.
Which two kinds of arteries are there?
Elastic and Muscular
Function of elastic arteries
Increase efficiency
Function of muscular arteries
Control distribution
What are the arterioles?
Terminal branches of the arteries
Examples of elastic arteries
Aorta Brachiocephalic Carotids Subclavian Pulmonary
What regulates blood flow in capillaries?
Precapillary sphincters
3 types of capillaries
Continuous
Fenestrated
Discontinuous
What drives embryonic vessel development
Angiogenic growth factors: (vascular endothelial growth factor, angiopoetin 1+2) which induce growth
Repulsive signals (plexin, semaphorin signalling, ephrin interactions) which prevent growth
Active signals - VEGF
How do you determine if a vessel is an artery or a vein? (receptor)
Ephrin-B2 receptor is only present on ARTERIES.
Ephrin-B4 receptor is only present on VEINS.
What do the first and second ‘aortic arches’ become?
They become minor head vessels.
The first aortic arch becomes a small part of maxillary.
The second aortic arch becomes artery to ear
What do the third aortic arches become?
Become common carotid arteries and proximal internal carotid arteries.
Distal internal carotids come from extension of dorsal aortae.
What happens to the right dorsal aorta and right 4th aortic arch?
The right dorsal aorta loosens connection with midline aorta and the 6th aortic arch, remaining connected to the right fourth arch. It acquires branch of 7th cervical intersegmental artery, which grows into the right upper limb. The right subclavian artery is diverted from the right fourth arch, right dorsal aorta and right 7th intersegmental artery.
Left dorsal aorta and Left 4th aortic arch
The left dorsal aorta continues into trunk as the descending aorta.
The left 7th cervical intersegmental artery grows into the left subclavian artery. The left subclavian artery is diverted from the left fourth arch, left dorsal aorta and left 7th intersegmental artery.
6th aortic arch
Right 6th arch may form part of the pulmonary trunk
Left arch forms ductus arteriosus - communication between pulmonary artery and the aorta.
Platelets and disease
Thrombosis Myocardial infarction Ischaemic Stroke Critical leg ischaemia Sudden death
What is atherogenesis?
formation of fatty deposits in arteries
What is atherothrombosis?
Blood clot within artery
What percentage narrowing ensures limited blood flow?
70%
What can atherothrombosis cause?
Angina
What can the inflammatory process driving the atherosclerosis lead to?
Thinning of capillary making it erode or rupture.
This leads to atherothrombosis since body wants to heal the rupture and form a thrombus.
What happens to a platelet when its activated?
Its shape changes. It changes from smooth discoid to spiculated (spikes/pointed) and pseudopodial.
The surface area increases
There is increased possibility of cell interactions because number of receptors increases.
There is increased affinity of receptor for fibrinogen (needed for platelet aggregation),
What receptors are on the surface of a platelet?
Glycoprotein IIb/IIa receptors
50,000-100,000 copies on resting platelet
Platelet action after atherosclerotic plaque rupture
Platelets adhere to damaged vessel wall. The collagen receptors bind to subendothelial collagen which is exposed. GPIIb/IIIa receptors on platelets bind to von Willebrand factor which is attached to collagen . The α2β1 receptor binds to collagen which slows the platelets down. Platelets come to a half and GPVI binds to collagen and activates platelets. Platelets release chemical which recruit other platelets and cause aggregation.
What is platelet adhesion?
A platelet spreading out on a collagen-coated surface
Platelet activation mechanisms
See M’s notes
COX-1 (Cyclooxygenase-1) enzyme
Mediates GI mucosal integrity
COX-1 –> Prostaglandin H2 –> Thromboxane A2
Thromboxane A2 released when platelet binds to collagen and mediates aggregation as well as stimulating contraction of the artery. Low doses of aspirin INHIBIT COX-1 pathway production of T-A2 which is good during/before heart attacks to prevent thrombus.
COX-2 (Cyclooxygenase-2) enzyme
Mediates inflammation
Mediates prostacyclin production, which inhibits platelet aggregation and affects renal function. keeps blood flowing.
COX-2/COX-1 => Prostaglandin H2 => Prostacyclin
Aspirin + COX
Low dose inhibits COX-1
High dose inhibits both COX-1 and COX-2.
What are the ADP receptors on platelets?
P2Y1
P2Y12
P2Y1 receptor
Link to Gq protein activating phospholipase C, mobilising calcium and initiates platelet activation
P2Y12 receptor
Linked to Gi protein which inhibits formation of cAMP, allowing for amplification of platelet activation.
What do the P2Y1 and P2Y12 pathways lead to?
The production of dense granules which get shunted to the surface of activated platelets and released. One of the content of these granules is ADP, which further activates the pathways greating a positive feedback loop. When GPIIb/IIIa binds to fibrnogen this causes further amplification.
What is an example of a receptor activated by Thrombin?
PAR-1
Platelet procoagulant activity mediated by changes to the membrane lipid bilayer
1) Platelet activation causes a change in the lipid bilayer.
2) Activation of PAR-1 receptor due to thrombin causes the release of calcium ions from intracellular stores.
3) This inhibits translocase and scramblase enzymes, causing amino-phospholipids to flip and express themselves onto the outer platelet membrane.
4) This exposure allows prothrombinase to bind to the membrane and convert prothrombin into thrombin.
What is the function of the fibrinolytic system?
Ensures a balance in the coagulation cycle
It is a system to break down the fibrinogen strands and dissolve the clot.
Fibronlytic system
Healthy endothelial cells release tPa (tissue plasminogen activator) which converts plasminogen into plasmin.
Plasmin breaks down fibrin into fibrin degradation products, and dissolvs the clot.
Inhibitors of the Fibronlytic system
PAI-1 blocks tPa
Antiplasmin blocks plasmin
α granules
- contribute to thrombotic response because they contain coagulation factors
- drive inflammatory response due to their inflammatory mediators (wound healing)
- contain P-selectin allowing platelets to bind to WBC
Platelet summary
See M notes page 28-29
Where can the apex beat be heard?
Left 5th intercostal space
Mid-clavicular line
Which chambers of the heart is anterior?
Mainly right ventricle
Which chambers of the heart are posterior?
Mainly left atrium and pulmonary veins
2 layers of the pericardium
Visceral
Parietal
What is a cardiac tamponade?
Restricts the rapid collection of pericardial fluid and impairs filling
What does pleural reflection allow?
Drainage of pericardial fluid from the left of the xiphisternum
What attaches papillary muscles of the ventricle to atriventricular valves?
chordae tendinae
What is the function of the coronary sinus?
drains blood from the heart muscle into the right atrium
What separates the smooth and trabeculated portions of the right atrium?
Crista terminalis
What is the Fossa ovalis?
The remains of the foramen ovale which was patent in foetal life
Where do coronary muscle cells cross link and join?
Intercalated discs
From where do coronary arteries arise?
Aortic root sinuses
How many main coronary arteries are there?
two - left and right
What does the left main stem divide into?
Left anterior descending and circumflex branches
Where does the left anterior descending branch?
The anterior interventricular groove
What does the left anterior descending give off?
Septal and diagonal branches to the septum and left ventricular myocardium
Where does the circumflex run?
Left atrioventricular groove
What does the circumflex give off?
Obtuse marginal branches to the posterolateral left ventricular wall
In 10% of people what does the circumflex provide?
Posterior descending artery
Where does the right coronary artery run?
Right atrioventricular groove
What does the RCA supply?
The sinus node
Atrioventricular node
Branches to the anterior right ventricle wall
What does distal RCA branch into?
Posterolateral and posterior descending arteries
Where does the posterior descending artery run?
Inferior septum
Left ventricle
Components of the Heart Conduction system
SA node
AV node
Bundle of His
Purkinje Fibres
What joins myocytes?
Intercalated discs (containing gap junctions and desmosomes)
Properties of myocytes
Branched tubular cell (strirated)
High mitochondrial density
Contains sarcromeres/myofibrils
Resting membrane potential of myocytes
Polarised
Negatively charged inside the cell (-90mV)
Unbalanced ion concentrations and active membrane pumps result in an external positive charge.
What does the pump in myocyte membrane do?
Na/K pump
3Na+ ions are transferred outside the cell and 2K+ transferred inside the cell maintaining the cell polarisation.
(Calcium also moves out with sodium).
What is the myocyte membrane permeable to?
Potassium ions.
The diffusion of potassium out of the cell allows negative polarisation inside the cell.
Myocardial action potential
Spread from one cell to another through gap junctions (connexins) and this activates other myocytes.
AV node and Purkinje fibres have similar action potentials but at a slower rate, therefore usually stimulated by potentials spreading from the AV node.
Summary of action potential process (6)
Depolarisation Repolarisation Propagation Excitation-contraction coupling Automaticity related to pacemaker AP Refractory period
Depolarisation
Rapid influx of sodium ions prolonged by influx of calcium ions
Repolarisation
potassium diffuses out of membrane
Propagation
Positive sodium ions depolarise adjacent cells and gap junctions
Excitation-contraction coupling
Release of calcium from T-tubules and sarcoplasmic reticulum.
Automacity related to pacemaker action potential
Slow sodium ion influx
Refractory period
Fast sodium ion and slow calcium ion channels close.
Phase numbers and their change in potential
0 = Rapid depolarisation (na+ inflow)
1 = Partial repolarisation
(K+ outflow/Na+ inflow stops)
2 = Plateau
(slow inflow of Ca2+)
3 = Repolarisation
(K+ outflow/inflow of Ca2+ stops)
4 = Resting potential
(K+ outflow only)
Refractory period (two kinds)
ABSOLUTE refractory period = inactivation of the sodium channels which close and do not open.
RELATIVE refractory period = sodium channels start to activate gradually. If a lot of channels reactivate another action potential can be stimulated.
Automaticity - pacemaker cells
Pacemaker cells have no true resting membrane potential and constantly drift towards the value of the action potential.
2 kinds of autonomic control
Sympathetic stimulation
Parasympathetic stimulation
What is sympathetic stimulation controlled by?
Adrenaline and noradrenaline and type 1 beta adrenoreceptors.
Increases adenyl cyclase => increases cAMP (Activating sodium and calcium channels and so allowing the the threshold to be reached sooner)
What does increased sympathetic stimulation result in?
Increased heart rate
Increased force of contraction
Large increase in cardiac output by up to 200%
What does decreased sympathetic stimulation result in?
Decrease in heart rate and decrease in cardiac output by 30%.
Blocking type 1 beta adrenareceptora (beta-blockers).
What is parasympathetic stimulation controlled by?
Acetylcholine
M2 receptors - inhibit adenyl cyclase => reduced cAMP (less sodium and calcium ions, activation of potassium ions)
What does increased parasympathetic stimulation result in?
Decreased heart rate
Decreased cardiac output ~50%
Decreased force of contraction
What does decreased parasympathetic stimulation result in?
Increased heart rate
Active Potential Propogation - why is it needed?
Effective cell-cell communication is critical for rapid, uniform conduction of cardiac action potentials because it allows the heart to contract co-ordinately.
How does active propogation happen?
There is a free flow of positive sodium ions between cardiomyocytes through gap junctions within the intercalated discs. This then allows neighbouring cells to reach their threshold and activate their own voltage gated sodium channels. Cannot bounce backwards due to refractory period.
Where is sinoatrial node located?
Posterior wall of Right Atrium
Conduction pathway SAN
Wave front conducted through right atrium by backward bundles to the left atrium and down to the atrioventricular node.
What does the SAN determine?
It is the primary pacemaker and normally determines the heart rate the heart beats.
Resting membrane potential of SAN.
What is the AP driven by?
negative
-55mV to -60mV
AP driven by slow Ca2+ channels because of slow Na+ inflow
Atrioventricular node
Transmits cardiac impulse between atria and ventricles.
Delays the impulse, allowing the atria to empty blood into ventricles.
Adaptations of AV node for its function
Less gap junctions - sodium ions move less quickly
Smaller fibres than atrial fibres = longer transmission
His-Purkinje System
Conduction down bundle of His to the left and right Purkinje fibres.
Spread from endocardium to pericardium.
Speed of conduction in His-Purkinje system - and why? How is it adapted to suit this speed?
Rapid!
This allows coordinated ventricular contraction from apex base.
Very large fibres and high permeability at gap junction.
Where in the heart can pacemaker cells be found?
SAN
AVN
HP system
Hierarchy of pacemakers
A slower pacemaker is blocked by a faster one
Myocardial Action Potential vs Skeletal Action potential
Key difference = the plateau phase.
Allows the heart to fill.
Mycardial contraction vs skeletal contraction
M is 15x longer
Excitation Contraction Coupling
purpose, which phase, what is it dependent on, what is the process
This stage is how an electrical impulse is translated into cardiac contraction. It’s dependent on calcium ions and happens during Phase 2 plateau.
Inward calcium current increases intracellular calcium concnetration, which activates receptors on sarcoplasmic reticulum leading to more release of calcium ions from the sarcoplasmic reticulum. Calcium ions bind to troponin C on actin filaments. This induces a conformational change exposing the actin-myosin binding site. Actin binds to myosin and cardiac contraction occurs.
What does an ECG show?
Changes in voltage over time (not action potential)
Baseline of ECG
Isoelectric point
= no net current flow in direction of lead
Positive deflection (up) from baseline
Net current flow towards lead
Negative deflection (down) from baseline
Net current flow away from lead
1 big square ECG
5mmx5mm
1 small square ECG
1mmx1mm
Typical speed and voltage settings ECG
Speed = 25mm/sec Voltage = 10mm/mV
Big/small squares (horizontal) and speed
5 big squares = 1 second
1 big square OR 5 small squares = 0.2 seconds
1 small square = 0.04 seconds
Big/small squares (vertical) and voltage
2 big squares = 1mV
1 big square = 0.5mV
What is an R-R interval
Time between beats/QRS complexes on ECG
P wave
atrial depolarization
less than 3 small squares
PR interval
Slow conduction between AV node and His-Purkinje system
3-5 small squares
120-200ms
QRS complex
Ventricular depolarisation
up to 120 ms
3 small squares
ST segment
The interval between depolarisation and repolarisation
T wave
Ventricular repolarisation
QT interval
Time of depolarisation and repolarisation
What causes QT interval to vary
heart rate
faster heart rate = shorter QT
Why can QT interval be prolonged? What are the values for prolonged QT in both men and women
Ischaemia, drugs, congenital issues
440 men
460 women
How do you perform an ECG?
Electrodes are placed on the skin, 6 chest leads and 4 limb leads.
V1: 4th intercostal space right side septum
V2: 4th intercostal space left sternal edge
V4: 5th intercostal space on midclavicular line
V3: half way between LSE and MCL leads
V6: 5th intercostal space on midaxillary line
V5: halfway between MAL and MCL
12 Lead ECG
aVF => +- 90° III => -60°, +120° aVL => -30°, +150° I => 0°, +180° aVR => +30°, -150° II => +60°, -120°
Lateral Leads
I
avL
V5
V6
Septal leads
V1
Anterior leads
V2, V3, V4
Inferior leads
II
III
avF
What can be deduced about electrical impulses from viewing a single electrode?
Electrical impulse is only briefly in the direction of electrode before it changes direction.
Wat can you say about electrical impulse for atria in comparison to ventricles
The impulse for the atria is smaller since atria are smaller and have less myocytes.
Abnormalities in P wave - tall peaked P wave
right atrial enlargement
Abnormalities in P wave - Bifid P wave
left atrial enlargement
Abnormalities in P wave- inverted P waves
non sinus origin (junctional or ecptopic atrial)
Abnormalities in QRS complex - broad complex
Ventricular origin (e.g. ventricular tachycardia)
Hyperkalemia (too much potassium)
Ventricular pacing
Left and right bundle branch block
Abnormalities in QRS complex - high voltage
ventricular hypertrophy (thickening of wall)
ST segment abnormalities: ST segment depression causes
Digoxin toxicity Hypokalaemia Ventricular hypertrophy Myocardial infarction Pulmonary embolism Raised intracranial pressure
Dextrocardia
Multiple -ve P waves
Low voltage V3-V6 with no progression
Can record right sided chest leads, which mirror the normal leads
Main components of the myocardium
Contractile tissue
Connective tissue
Fibrous frame
Specialised conduction system
What does myocardial metabolism rely on?
Relies on free fatty acids during aerobic metabolism (efficient energy production)
Myocardial metabolism during hypoxia
During ypoxia, there is no FFA metabolism, thus anaerobic metabolism ensues. This relies on metabolising glucose anaerobically producing energy sufficient to maintain the survival or the affected muscle without contraction.
Ultrastructure of the myocardial working cell: how are the contractile proteins arranged?
In a regular array of thick myosin and thin actin filaments (myofibrils)
The sarcomere
The functional unit of the contracile apparatus. It is the region between a pair of Z-lines, containing two half I-bands and one A-band.
The sarcoplasmic reticulum
A membrane network that surrounds the contractile proteins. It consists of the sarcotubular network at the centre of the sarcomere and the subsarcolemmal cisternae (T-tubules and sarcolemma) so that Ca2+ ions are always available.
What lines the transverse tubule (T-tubule) system?
A membrane that is continuous with the sarcolemma, so that the lumen of the T-tubules carries the extracellular space towards the centre of the myocardial cell.
Where is mitochondria found in myocardium
In between myofibrils.
A-band
The region of the sarcomere occupied by the thick filaments (myosin)
I-band
Occupied only by thin actin filaments that extend towards the centre of the sarcomere from the Z-lines. It also contains tropomyosin and troponins.
What attaches atin filaments to the Z-lines?
Titin proteins, which provide elasticity.
What happens when titin proteins are damaged?
Elongation of the muscle => heart failure.
Summary of contraction mechanism
- Depolarisation of the cell membrane.
- Influx of Ca2+ inwards
- Ca2+ binds to troponin.
- Troponin changes shape and troponin-tropomyosin complex is lifted from the actin groove
- The actin-myosin binding site is exposed
- Actin moves closer to the centre of the sarcomere, allowing for myosin bridge to bind to actin and causes contraction
- Sliding of actin over myosin by ATP hydrolysis through the action of ATPase in the head of the myosin molecule. These heads form the cross bridges that interact with actin, after linkage between calcium and troponin, and deactivation of tropomyosin and TnI (changed troponin).
Repolarisation muscle
Cells spend energy to removed Ca2+ from troponin, allowing it to inhibit actin-myosin interaction. The bridges are separated and actin is moved back. Muscle relaxes.
Myosin structure
2 heavy chains (responsible for the dual heads)
4 light chains
The heads are perpendicular on the thick filament at rest, and bend towards the centre of the sarcomere during contraction.
Alpha and beta myosin.
Actin structure and properties
Globular protein
Double-stranded macromolecular helix (G) - creates a groove where the myosin acts which is covered by the troponin-tropomyosin complex.
Tropomyosin structure and properties
Elongated molecule, made of two helical peptide chains.
It occupies each of the longitudinal grooves between the two actin strands.
Troponin TnI
forms complex with tropomyosin to inhibit actin and myosin interaction
Troponin TnT
binds troponin to tropomyosin
Troponin TnC
high affinity calcium binding sites, signalling contraction
Circulation in the heart
Superior + inferior Vena Cava bring deoxygenated blood to right atrium
Blood moved across tricuspid valve to right ventricle
Blood is squeezed out of right ventricle, through the pulmonary artery into the lungs across the pulmonary valve
Oxygenated blood comes back to the heart through the 4 pulmonary veins into the left atrium
Moved down into the left ventricle across the mitral valve
Left ventricle squeezes blood out the aorta across the aortic valve into systematic circulation.
Cardiac cycle overview of stages
- Isovolumic contraction
- Ejection
- Isovolumic relaxation
- Rapid inflow
- Diastasis
- Atrial systole
ECG and cardiac cycle
P - atrium depolarised; occurs before atrial contraction
QRS - ventricle depolarisaed; occurs just as ventricles begin to contract
T - repolarisation
First heart sound
Closure of the mitral valve at the end of diastole + beginning of isovolumetric contraction
Second heart sound
Closure of the aortic valve at the end of ventricle emptying and beginning of isovolumetric relaxation
Ventricular pressure + LV Conctraction
During isovolumetric contraction the volume of the ventricle does not change, both the valves are closed. The ventricle changes shape as it squeezes. This raises the pressure to open the aortic valve.
How much blood remains in ventricle after it contracts?
30%
Ventricular pressure during left ventricle relaxation
At the start of relaxation and reduced ejection the aortic valve shuts. The ventricle wall continues to relax and lose pressure with 1/3 of normal volume. Rapid LA filling causes blood to passively move into ventricles down pressure gradient when mitral valve opens. During diastasis the pressure in ventricles starts rising and pressure in atrium and ventricle are equal. There is no movement of blood. Atrial booster is contraction of atrium to squeeze in extra blood.
What is a 4th heart sound indicative of?
Stiff atria/heart failure
Ventricular contraction - systole
Steps
Wave of depolarisation arrives and opens the L-calcium tubule (on an ECG, this is the peak of R). Calcium ions arrive at the contractile proteins. Left ventricle pressure rises to above left atrial pressure. The mitral valve closes. Left ventricular pressure rises to above aortic pressure. Aortic valve opens and ejection starts.
Ventricular relaxation - diastole
STEPS
LVp peaks then decreases. The influence of phosphorylated phospholambdan; cytosolic calcium is taken up into the sarcoplasmic reticulum. This creates a phase of reduced ejection. Aortic flow is maintained by aortic distensibility. Aortic pressure exceeds LVp, aortic valve closes.
Ventricular filling - steps
LAp is greater than LVp, mitral valve opens, rapid filling starts. Ventricular suction may also contribute to E filling.
Diastisis - LVp = LAp. Filling temporarily stops. Filling is renewed when atrial booster raises LAp creating a pressure gradient.
Preload
Load present before left ventricle contraction has started; amount of stress in ventricle.
Afterload
Load after the ventricle contracts.
Contractility (inotropic state)
The state of the heart which enables it to increase its contraction velocity, to achieve higher pressure, where contractility is increased.
Elasitcity
the myocardial ability to recover its normal shape after removal of systolic stress.
Compliance
compliance = how easily a chamber of the heart or the lumen of a blood vessel expands when it is filled with a volume of blood
the relationship between the change in stress and the resultant strain.
Diastolic distensibility
The pressure required to fill the ventricle to the same diastolic volume.
The pressure-volume loop
contractility in the end-systolic pressure volume relationship, while compliance is reflected at the end diastolic pressure volume relationship.
Pulmonary and bronchial circulation
Dual blood supply
Pulmonary circulation from right ventricle
Bronchial circulation takes 2% of left ventricle output.
Pulmonary vs Systemic arteries: vessel wall
Pul. = thin System = thick
Pulmonary vs Systemic arteries: muscularization
Pulmonary = minor Systematic = significant
Pulmonary vs Systemic arteries: need for redistribution
Pulmonary = not in normal state Systematic = yes
mPAP
mean pulmonary arterial pressure
PAWP
pulmonary arterial wedge pressure (estimate of LA pressure)
mPAP - PAWP = …
CO X Pulmonary vascular resistance
What happens to mPAP and CO during exercise? Why is there a difference?
mPAP remains stable
CO increases signifiantly.
This occurs due to resistance falling by recruitment and distension of capillaries in response to increase pulmonary artery pressure.
Hypoxaemia
low oxygen in blood
Type 1 respiratory failure values of pO2 and pCO2
(O2) less than 8kPa
(CO2) less than 6kPa
Type 2 respiratory failure values of pO2 and pCO2
pO2 less than 8kPa
CO2 more than 6kPa because with Type II there is a problem with removing CO2.
Causes of hypoxaemia
Hypoventilation
Diffusion impairment across alveoli capillary membrane
Shunting (blood going through without ventilation)
Mismatch between ventilation and perfusion.
Hypoventilation
(occurs during type II RF) Failure to ventilate the alveoli. Leads to muscle weakness. Obesity. Loss of respiratory drive. Examples in motor neurone disease, kyphosis/scoliosis
Diffusion impairment (hint: 3 types)
- Gaseous diffusion - pulmonary oedema (fluid build up in alveoli). Pulmonary fibrosis increases thickness of lungs.
- Blood diffusion - anaemia
- Membrane diffusion - interstitial fibrosis
V/Q = 1
Optimal gas exchange, occuring when regions of lung are ventilated in proportion to their perfusion.
V/Q mismatch cases
Pulmonary embolism
Asthma
Pneumonia
Pulmonary oedema
V/Q > 1
(Dead space)
Ventilation in excess of perfusion.
However, pulmonary blood is passing ventilated alveoli and PaO2 is normal.
V/Q 0-1
Perfusion in excess of ventilation.
increasing PAO2 will increase PaO2.
V/Q = 0
shunt
Mixed venous blood entering the systemic circulation without being oxygenated vis passage through the lungs.
PaO2 falls.
Physiological shunt
Bronchial arteries - blood not taking part on gas transfer
Intracardiac shunt
Eisenmenger’s syndrome
Ventricular septum defect (VSD).
Pulmonary shunt
Arterio-venous malformation (skipping the capillaries and so not oxygenating the blood).
Complete lobar collapse.
Eisenmenger’s syndrome
Baby will not be born blue, as oxygenated bloood in the left ventricle moves to the right ventricle and out of the pulmonary artery. However excess volume under high pressure in the pulmonary artery damages it, creating narrowing, increasing resistance and pressure. Blood then goes from RV to LV, and patients present with cyanosis (blueish discolouration of skin). Rasping murmur will be heard. Another symptom of R/L shunt is clubbing of the nails, and polycythaemia (excess red cells with secondary erythrocytosis).
Hypoxic Pulmonary vasoconstriction
Local action of hypoxia on pulmonary artery wall. Weak response as little muscle. Aims to improve V/Q matching.
Diseases of the pulmonary circulation
Pulmonary embolism
Pulmonary hypertrophy
Pulmonary arteriovenous malformations
Pulmonary embolism
A large thrombus = can block the lungs centrally.
A smaller clot is not as severe but causes infarction.
How is a pulmonary embolism diagnosed?
CT scan
V/Q scan
Inhaling radioactive gas to see even ventilation.
Virchow’s Triad
3 things that make you more likely to have bloodclots; risk increases with the more of these you have.
- Circulatory Stasis (blood not moving in the legs properly)
- Endothelial injury
- Hypercoagulable state (increased risk of bleeding thrombophilia (more likely to clot)).
Pulmonary arterial hypertension progression
Normal pulmonary artery -> intermedia layer thickens.
The right ventricle increases in size
Left ventricle becomes smaller.
Increased pulmonary ventricular resistance.
What does pulmonary arteriovenous malformation (shunt) cause
Hypoxaemia
Blood pressure equation
BP = CO X Total peripheral resistance
Pulse pressure equation
systolic - diastolic p
Mean arterial pressure equation
Diastolic pressure + 1/3 pulse pressure
Frank-Starling Mechanism.
Stroke volume increases as end-diastolic volume increases due to length-tension relationship of muscle. As the end-diastolic-volume increases, stretch increases and the force of contraction increases. Cardiac muscle at rest is not at is optiumum length.
↑VR = ↑EDV = ↑SV = ↑CO (even if HR constant)
What factors effect blood volume
Renin-Angiotensin-Aldosterone system
ADH
Adrenals and kidneys
How is blood pressure measured?
using a sphgmomanometer using bracial artery
Control of pressure
Autoregulation Local mediators Humoral factors Baroreceptors Central neural control
Myogenic autoregulation - what is it and what does it regulate?
Stretching of the arteriole.
Regulates the constant flow despite perfusion pressure changes.
Where is myogenic autoregulation excellent, moderate and poor?
Excellent = renal/cerebral/coronary Moderate = skeletal muscle/splanchic Poor = cutaneous (skin)
Balancing intrinsic and extrinsic controls: brain &heart
Intrinsic control dominates to maintain bloodflow to vital organs
Balancing intrinsic and extrinsic controls: skin
Blood flow is important in general vasoconstrictor response and also in responses to temperature (extrinsic) via hypothalamus.
Balancing intrinsic and extrinsic controls: skeletal muscle
Dual effects: at rest, vasoconstrictor (Extrinsic) tone is dominant; upon exercise, intrinsic mechanisms predominate (Rapid release of blood into muscles)
Local humoral factors (vasoconstrictors)
Endothelin- 1
Internal blood pressure (myogenic contraction).
Local humoral factors (vasodilators)
Hypoxia Adenosine Bradykinin NO Potassium ions Carbon dioxide [H+] Tissue breakdown products
What is the endothelium derived relaxing factor?
Nitric oxide, a potent vasodilator, which is produced by the endothelium.
L-Arginine is converted into NO by NO synthase.
Prostacyclin
potent vasodilator
Endothelin
potent vasoconstrictor
Circulating (hormonal) factors - Vasoconstrictors
Epinephrine
Angiotensin II
Vasopressin
Circulating (hormonal) factors - Vasodilators
Epinephrine
Atrial Natriuretic peptide (ANP)
Baroreceptors
pressure receptors
Primary baroreceptors
Arterial
=> carotid sinus and aortic arch
Secondary baroreceptors
veins, myocardium, pulmonary vessels
What is baroreceptor firing rate proportional to?
MAP and PP, integrated in the medulla
How do arterial baroreceptors affect central control:
An increase in blood pressure leads to an increase in firing rate leading to an increase in parasympathetic nerve supply (?) and decrease in sympathetic nerve supply (?) leading to a decrease in cardiac outflow and total peripheral resistance and thus a decrease in blood pressure.
Arterial baroreceptors
Key role in short-term regulation of BP; minute to minute control, response to exercise, haemorrhage.
What happens if arterial pressure deviates from the norm?
If arterial pressure deviates from the norm for a few days the baroreceptors adapt or reset to new baselin pressure, for example in hypertension.
Cardiopulmonary baroreceptors
Atria, ventricles, pulmonary artery
Stimulation leads to a decrease in vasoconstriction. Also leads to decrease in angiotensin, aldosterone and ADH/vasopressin, leading to fluid loss.
Main neural influence on medulla
Baroreceptors Chemoreceptors Hypothalamus Cerebral cortex Skin Changes in blood [O2] and [CO2]
Which higher centers do CV reflexes require
hypothalamus
pons
Effect of stimulation of anterior hypothalamus on CVS
Decrease in blood pressure
Decrease in heart rate
Effect of stimulation of posterolateral hypothalamus on CVS
Increase in BP and HR
How can the cerebral cortex affect blood flow and pressure?
Stimulation of CC usually increases vasoconstriction, but emotion can increase vasdilation and depressor responses e.g. blushing or fainting. Effects mediated via medula, but some also directly.
Central chemoreceptors
Chemosensitive regions in the medulla. An increase in PaCO2 leads to vasoconstriction, an increase in peripheral resistance and an increase in blood pressure.
A decrease in PaCO2 leads to a decrease in medullary tonic acitivty and a decrease in BP.
Fainting (neuro-cardiogenic syncope) symptoms, physiology, signs and treatment
Nausea, air hunger, sweating, light headed.
Fall in HR and venous pooling
Collapse due to decrease in CO.
HR falls, CO falls, BP falls, perfusion to brain reduced.
Treatment = lay supine and elevate limbs to increase VR.
Blood loss + homeostasis
Perfusion to brain must be maintained so local vasoconstriction. Cardiac output and blood pressure is maintained by increasing the heart rate.
Increase in sympathetic outflow.
Widespread cutaneous vasoconstriction (skin).
Eventually, the body goes into ‘shock’ i.e. BP down, pulse up, organ hypoperfusion and death.
Treatment: rapid volume replacement
