RBF Flashcards
What is respiratory failure?
When the lung fails to oxygenate the arterial blood adequately and/or fails to prevent undue CO2 retention
What are the causes of hypoxaemia?
Reduced PiO2 Hypoventilation VQ mismatch RL shunt Diffusion problem
What can cause hypoventilation?
Decreased respiratory drive
Neuromuscular incompetence- due to issues with nerves themselves, NMJs or the muscles (electrolytes, malnutrition, length tension abnormalities)
Or abnormal load- do due increased resistance, elastence, chest wall elastic load, or minute ventilation load
What is the alveolar gas equation?
PAO2 = (Pb - PH2O) x FIO2 - PACO2/R + k
At sea level on air this equates to
20 - PaCO2/0.8 - PaO2
What is alveolar capillary block and how does it cause SOB exacerbated by exercise?
It is due to buildup of scar tissue etc in the interstitial space between the alveolar wall and the capillaries, making it more difficult to diffuse O2 from the air into the blood
Normally, it takes a small amount of time for the saturation of blood to near the PAO2 as it travels through the pulmonary capillaries
In cases like these, it takes longer to reach equilibrium. When the patient exercises, it results in even less transit time, meaning the blood often leaves less saturated than normal
How can diffusion issues cause hypoventilation?
Alveolar capillary block- diffuse interstitial lung disease
Capillary volume/Hb issues- pulmonary hypertension and anaemia
Loss of diffusing surface- emphysema
What are the equations related to diffusion in the lungs?
Vgas = A/T x D x (P1-P2)
D =Sol sqMW
1/DLCO = 1/DM + 1/O x VCapillary
What are the different stages of Oxygen consumption affected by?
PiO2 is affected by altitude and fraction of O2 in the air
PAO2 depends on alveolar ventilation and PACO2- it’s a pump, so can show a normal A-a gradient even with respiratory failure
PaO2 is affected by gas exchange, in the A-a gradient. This is impacted by VQ mismatch, RL shunt and diffusion factors
Tissue PO2 is affected by extraction, perfusion, and Hb or saturation
What is homeostasis and how is it managed?
The capacity to regulate the internal environment to maintain stable, constant conditions
It is actively controlled, with feedback mechanisms regulating the output of a process, and sensors detecting this to feed back to modulate the actions of an effector
What is equilibrium and how does this relate to the cardiovascular system?
Closed systems containing two or more processes whose outputs are determined by a common parameter can operate at a stable equilibrium
Eg. MRAP affects the extent of right heart filling (and CO) as well as amount of venous return
As MRAP increases, VR falls and CO increases to a max.
As MRAP falls, CO falls and VR rises until the pressure inside the veins is equal to outside- this is when they begin to close off and a plateau is formed
They must operate at an equilibrium where VR is the same as CO
How does cardiovascular equilibrium change?
During exercise, there is a degrease in PVR and an increase in venous muscular activity, helping to drive blood back to the heart. This causes an increase in MRAP, so increased cardiac filling and an increase in equilibrium point
More vigorous cardiac function causes a reduction in MRAP, allowing an increased venous return until the point of plateau
How does circulatory distribution change during exercise?
Resistance to blood flow changes, preferentially diverting blood to the muscles and heart at the expense of the GI tract, kidneys and liver.
Blood to the brain remains the same
How does the ANS affect cardiovascular homeostasis?
The CNS has receptors around the body that receive information and feed it back to the brain.
It can then activate sympathetic or parasympathetic nerves to modulate the function of specific organs
Describe the RAAS system and what activates it
Renin is released from the JGA due to sympathetic stimulation, decreased arteriolar pressure, or decreased sodium at the macula densa
This converts angiotensinogen to angiotensin I, which is then converted by ACE in the lungs to angiotensin II
What are the actions of angiotensin II?
Activates sympathetic pathways in the brain as it crosses the BBB
Facilitates neurotransmission at paravertebral ganlia
Increases synthesis and release of NA
Acts to cause constriction of vascular smooth muscle
Increases formation and release of aldosterone to increase absorption of sodium in the renal tubules- increases fluid retention and blood volume
Facilitates ADH secretion and stimulates thirst
What are the actions of ADH?
Regulates renal water handling
Can act as a vasoconstrictor
Where are ANP and BNP synthesised and in response to what?
ANP= Atrial myocytes
BNP- ventricles
Stimulated in response to cardiac distension, sympathetic stimulation, angiotensin II or endothelin
What are the actions of the natriuretic peptides?
Natriuresis and diuresis increased GFR and filtration fraction Inhibition of renin Vasodilation Results in reduced blood volume, arterial pressure, central venous pressure, pulmonary capillary wedge pressure and cardiac output
What does NEP do?
A circulating enzyme that degrades natriuretic peptides. Inhibiting it increases and potentiates natriuretic peptids
What is the use of anticoagulant drugs?
Used for arterial disease such as CAD, cerebrovascuular disease, and peripheral vascular disease
Used in thrombo-embolic disease, for atrial fibrillation, DVT/PE, and for prosthetic cardiac valves (metal only)
Describe unfractionated heparin and what it can be used for
It is a large molecule with variable weights (as it is produced in different animals’ tissues)
It is an ionic compound so it should always be given IV
Used for acute coronary syndromes, in thromboembolism and as a temporary warfarin replacement during pregnancy
How does unfractionated heparin work?
It binds to and increases the activity of anti-thrombin III, which inactivates thrombin, Xa, IXa, XIa and XIIa
This requires its dosing to be monitored with APTT
It has a rapid onset and offset with a short half life but variable bioavailability- it may bind unpredictably to cells and plasma proteins
Must be maintained within a therapeutic range of 50-80s APTT
What are some adverse effects of unfractionated Heparin and how does it get reversed?
It can cause bruising or bleeding
Heparin induced thrombocytopenia- and autoimmune phenomenon as heparin epitopes are similar to platelets, resulting in bleeding or serious thromboses.
Requires checking of platelets every 2 days
Heparin is reversed by giving protamine (dissociates heparin by irreversibly binding) if actively bleeding, otherwise simply stopping heparin will be enough after 30 mins.
Describe low molecular weight heparins and its advantages
Generated by depolymerisation of unfractionated. They bind to antithrombin III but do not inactivate thrombin, specifically acting on Xa.
It has a reliable dose-effect relationship and does not require monitoring.
It has a higher bioavailability and doesn’t bind to other blood proteins etc
Longer biological half life, given subcutaneously so can be done at hospital and home, and has lower risk of thrombocytopenia and bleeding
Dosing is also only based on weight rather than APTT
What are the pros and cons and uses of LMWH compared to UF heparin
Pros are improved pharmacokinetics, less monitoring requirement, as well as less risk of thrombocytopenia and osteoporosis
Cons are that APTT cannot be used to monitor it, it cannot be reversed by protamine, and it is harder in renal failure as LMWH are cleared by kidneys while UF heparin is cleared by reticuloendothelial system
Both are used in stemi, initial DVT/PE, and as a warfarin alternative. LMWH is also used for catheterisation and nstemis.
What is warfarin and how does it act?
It is a vitamin K antagonist, with S isoforms more active than R
It inhibits synthesis of coagulation factors VII, IX, X and II, but has a slow onset- so while it is waiting to kick in, heparin is used
It is metabolised by CYP450 and crosses the placenta
What is warfarin used for and for how long?
It is used for thrombses, and for preventing these in cases of mechanical heart valves and atrial fibrillation (lifelong)
In terms of warfarin duration of treatment in DVT, it used for months for risk factors or first DVT. It is used lifelong in thrombophilia and potentially cancer cases
What are the side effects of warfarin?
Intracrainal or GI haemorrhage (more likely in oder age groups, those with cerebrovascular disease, previous GI ulcer/bleed, liver/renal damage, and high target INR
Contraindicated by pregnancy, high risk of haemorrhage (uncontrolled alcohol, dementia, high falls)
How is warfarin monitored?
By INR: Ratio of patient’s PT to mean normal PT.
Those with prosthetics and recurrent thromboses have a higher target INR than those with a single venous thrombosis episode
What are some interactions with warfarin?
Most increase effect of warfarin’s effect by inhibiting CYP450
Eg. intermittent alcohol, analgesics, amiodarone
Some inhibit warfarin by increasing P450- eg. prolonged alcohol, barbituates
How can warfarin (High INR) be reversed?
Giving vitamin K if bleeding is not severe Giving prothrombinex (concentrate containing vitamin K dependent factors) if lifethreatening
What are some of the downsides of warfarin?
Narrow therapeutic window
Lifetime risk of haemorrhage increases
Drug interactions
Needs regular INR
Describe dabigatran and its usage
It’s a prodrug that is converted to an inhibitor of coagulation by gut, plasma and liver esterases
It isn’t P450 dependent, but is excreted renally
It is used to treat and prevent VTE, for atrial fibrillation, but NOT for mechanical valves
Bleeding can be managed by monoclonal IV antibody idarucizumab
Describe VQ mismatch and what it means for CO2 and CCO2
VQ mismatch is a ratio of the perfusion of alveoli to their ventilation
An alveolus that is ventilated but not perfused has a ratio of infinity, and can be considered dead space as it does not affect gas exchange at all
An alveolus that is perfused and ventilated has a ratio of 1, and gives a normal CO2 and CCO2.
An alveolus that is perfused but not ventilated has a ratio of 0, and is called venous admixture, as the blood being combined in later circulation is technically venous. It has a low CO2 and high CCO2.
Overall, this has the effect of slightly lowering CO2 and keeping CCO2 normal (due to the shape of its dissociation curve). However, this regulation is decreased in a loss of competence or introduction of an abnormal load.
Describe COPD and its effects
It is characterised by airflow obstruction that is not fully reversible
It is progressive, related to an abnormal inflammatory response
Symptoms include chronic mucus hypersecretion, emphysema and small airway inflammation, with increased and hypertrophied goblet cells and destruction of lung parenchyma
What happens of a poorly ventilated alveolar system becomes worse or abnormal load is introduced?
PaCO2 will increase, causing a loss of CO2 drive and respiration to depend on hypoxic drive
If O2 is administered due to SOB, it will cause loss of drive, causing reduced ventilation, hypercapia, and potentially respiratory and metabolic acidosis.
CO2 increases can show intracellular acidosis, hypoxia, and sleep depravation.
What are the consequences of a respiratory acidosis?
Reduced cardiac and respiratory muscle contractility, reduced endurance time, arterial vasodilation, increased cerebral blood flow, arrhythmias etc.
What is the difference in oxygen and co2 dissociation curves and what does this mean?
Oxygen’s dissociation is sigmoidal, but normally CO2 is on the high side, so when hyperventilating, the Co2 only moves along the flat part of the curve
CCO2 is diagonal, so when PCO2 decreases during hyperventilation, CCO2 also decreases
Describe RL shints
It is an anatomical abnormality shnting blood from the RHS to LHS of the heart
Distinguished from VQ mismatch b administering 100% O2- VQ mismatch will always increase with 100% O2, while a shunt increases much less as it worsens
This is because the shunted blood does not see the added O2, and so depresses the arterial PO2- however, it can still help by increasing the dissolved oxygen content, .
Shunting will show cyanosis due to desaturated Hb and ruddiness due to increased Hb concentration due to chronic hypoxaemia
Describe the differences in vascular structure throughout the vascular system
The highest proportion of smooth muscle in the vessel walls is located in the small arteries and arterioles, while the postcapillary vessels have the smallest
The microcirculation is in intimate contact with the tissue it supplies
Describe the innervation of the vascular system
Sympathetic adrenergic nerves supply all vascular beds in the body. However, its extent varies widely, with arteries and arterioles directly innervated, and veins more sparsely (increasing with size), and no direct capillary innervation.
Parasympathetic cholinergic innervation of precapillary vessels exists in some organs.
How do the precapillary vessels change fluid extrusion/reabsorption?
The small arteries and arterioles are the site of the largest pressure change across the whole vasculature. Therefore they contribute the most to resistance
Vasodilation of these precapillary vessels reduces resistance and increases blood flow, and vice versa. Constriction means that energy dissipated as blood flows through the small arteries and arterioles is increased, resulting in a reduction in mean hydrostatic pressure.
Precapillary dilation leads to extrusion of fluid, and vice versa
What is local autoregulation of the vasculature and what does it do?
The organ has an intrinsic tendencey to maintain constant blood flow despite change in perfusion pressure
As perfusion pressure increases, there is an increase in blood flow that then returns to the previous level, often within a few seconds and vice versa.
This varies however- cutaneous circulation exhibits almost no autoregulation, while the cerebral circulation is tightly maintained
What is reactive hyperaemia?
After a short period of blood vessel occlusion, blood flow rises above the level of flow before the occlusion, for a period proportional to the duration of the occlusion
Describe myogenic control of the vasculature
An increase in transmural pressure on a blood vessel results in increased vascular contraction and vice versa
Responses of this nature are most potent in medium arterioles and small to medium veins. This is done as the pressure increase distends the vessel walls, depolarising the vascular smooth muscle cells and causing contraction
Describe metabolic control of the vasculature
Local vascular contraction is dependent on the perivascular concentration of metabolites. This is determined by the rate at which they are produced compared to the rate at which they are washed out.
More active cells produce more adenosine, etc, which stimulates contraction of nearby smooth muscle cells
How does the vascular endothelium achieve local control?
The endothelium releases nitric oxide, which acts on VSM to increase intracellular cGMP, causing relaxation.
It can also release endothelin, which causes Ca2+ channel agonism and vasoconstriction
How does noradrenaline act on vascular smooth muscle?
There are three options for its binding to the VSM membrane channels
- A1 receptors. This is linked to the G protein Gq, which activates phospholipase, increasing IP3 and DAG. This causes increased Ca2+ and vasocontstriction
- A2 receptors. These are linked to Gi proteins, which inhibit adenylate cyclase, decreasing cAMP, increasing Ca2+ extrusion and sequestering it intracellularly. This leads to vasodilation
What factors excite vs inhibit the release of NE from the nerve terminal?
Excitatory: Ang II, adrenaline
Inhibitory” ACh adenosine, dopamine, histamine, PGE1/2
Describe how cholinergic nerves act on the vasculature
Activation releases ACh, binding the the M3 receptors in vascular endothelium, stimulating NO synthesis. However, if it binds to M2, it causes vasodilation
Sympathetic cholinergic nerves are similar, but innervate precapillary vessels in skeletal muscles and sweat glands, leading to vasodilation and sweating
How does adrenaline vs noradrenaline affect the circulation?
NA causes widespread vasoconstriction excep for the coronary and cerebral circulations
A causes this as well as vasodilation in skeletal muscles and splanchnic circuits
This is done as B2 receptors (which stimulate cAMP to do vasodilation) have a higher affinity for adrenaline than noradrenaline. These receptors are located only in skeletal and splanchnic circuits
How do skeletal muscle vessels vasodilate during exertion?
At moderate and high exercise levels, sympathetic stimulation is ineffective, as the concentrations of extracellular metabolite become so high in the working tissue that they cause vasodilation as well as inhibiting sympathetic transmission
There may also be action of sympathetic nerves on B2 receptors
The metabolites don’t really affect postcapillary vessels
The speed and magnitude of hyperaemia is not totally explained by these mechanisms!
Describe how skin circulation is affected by changes in innervation
The skin has low capillary density and lots of shunting.
Blood flow at rest is even greater than requirements. only a receptors are present, and therefore is powerfully influenced by sympathetic innervation
Affinity of a receptors for NA decreases as skin temperature rising, leading directly to increased cutaneous blood flow
The sweat glands also activate the kinin cascade, increasing blood flow and improving heat loss
Describe how the cerebral curculation maintains its tight link to metabolism and blood flow
Total blood flow remains very constant, but regional variations may be marked. Perivascular pH and CO2, O2, K+ are used in matching the two. High PaCO2 causes increased flow and vice versa.
Catecholamines have little effect as they cannot penetrate the BBB. Sympathetic innervation provokes only transient results
Interstitial fluid volume and intracranial pressure can also cause alterations in flow- similarly to compartment syndrome
Describe reynaud’s disease
Associated with prolonged vasoconstriction of digital arteries of the hand when exposed to cold stimulus
Due to inappropriate responsiveness of a adrenergic receptors
In chronic disease, skin ulcers and bone necrosis may occur due to abnormal vessel structure
Describe how FEV1 changes as an asthmatic exercises and then rests
Initially it goes up, as sympathetic stimulation bronchodilates the airways
Then there is a massive drop in FEV1 as airway hyperresponsiveness causes histamine and leukotrine release, resulting in airway narrowing. This can be mediated by smooth muscle contraction or by increased thickening of mucus
Why does asthma present with a wheeze?
This occurs because when an asthma attack occurs, flow becomes proportional to elastic pressure over resistance.
The pleural pressure must increase as expiration is more and more forced, until the point at which pleural pressure equals the pressure within the airway- this then forces the airway to collapse, and expiration becomes effort independent as changing the force no longer increases the flow
Describe the interpretation of flow-volume curves
Flow is on the y axis, volume on the x axis
Expiratory flow sees the graph peak upwards sharply to PEF, and then decrease through FEV1 and to minimum. Inspiration has less flow peak, but just a curve underneath. Tidal breathing tends to be within the middle of this graph.
The first half of the Fexpiratory descent line is effort dependent, while the lower part is effort independent.
What is the difference between a healthy flow-volume curve and an unhealthy flow-volume curve?
A reduced PF
Reduced FEV1
Reduced FVC, but FEV1 reduced to a greater extent
Increase in residual volume
Tidal breathing occurs at higher lung volumes, esp in emphysema as it allows the airways to stretch, increasing use of elastic pressure to drive outflow
What are the advantages and disadvantages to using FEV1 and PEF as the measure of lung function?
FEV1: Much better for distinguishing abnormality and relatively effort independent
PEF is simple and cheap, but there is a wide normal range and it is relatively effort dependent.
Describe the area of the pressure-volume curve of breathing tidally and at high lung volumes, and its implication for pathology
Normally we breathe in the steep part of the sigmoidal pressure volume curve, but at high lung volumes this is flatter, indicating lower compliance. This means it takes more generation of pressure to maintain the same lung volumes in pathology
Describe why an inspiratory wheeze might occur?
Normally due to extrathoracic limitation, as both the elastic recoil must be overcome as well as the airflow limitation.
What causes inspiratory crackles?
Due to thickened interstitial barrier between alveloli capillaries- the basal airways close off during tidal breathing, and must be ‘popped’ open once the lung reaches a certain pressure. The noncompliant airways all open together, causing a crackle
Describe why shortness of breath is a common issue in COPD/ interstiatial lung disease
SOB mostly correlates with increased work of breathing, rather than actual hypoxaemia
Normally, tidal volume and pressure has an increasing slope. In fibrosis, this slope is flatter, meaning there is increased elastic work of breathing that needs to be overcome as the lung is less compliant. When exercising, this increases work of breathing markedly, so resp rate increases as it is easier to maintain adequate breathing in this way.
How does cardiac depolarisation move through the heart?
The wavefront spreads from endocardium to epicardium and from apex to base
It moves from SA node to atria, to AV node, to bundle branches to purkinje fibres
What features maintain sinus rhythm in the heart?
- Suppression of lower frequency pacemakers. While AV cells have an unstable membrane potential and could act as pacemakers, the SA node drives them because it has the fastest spontaneous rate. This suppresses the automaticity of lower pacemakers.
- Programmed excitation via the conduction system
- A prolonged refractory period in the myocardium
Describe how an arrhythmia may be generated
Arrhythmia is defined as any deviation from normal sinus rhythm.
It may be caused by early pacemaker discharge or activity triggered by an unstable RMP. This is caused by delayed or early afterdepolarisations. These tend to occur in the relative and supernormal refractory periods, though these are poorly conducted. Ectopic beats must be generated by numerous cells synchronously
It can also be due to impulse conduction, such as AV/bundle branch block (slowed heart rate) or reentry (altered time course of spatial or temporal repolarization)
Describe atrial flutter
Caused by a single atrial reentry circuit and assoc with fast atrial rate, increasing the likelihood of partial AV block
It shows sawtoothed waves between QRS complexes
Describe atrial fibrillation
Rapid disorganised atrial activation, with not all being conducted to ventricles and so causing a disordered ventricular rhythm. It is more common after lesions, CHF or in the elderly. Significant risk of clots and PE/Stroke
Describe ventricular tachycardia and fibrillation
Can occur in myocardial ischaemia, due to remodelling after healed infarction, heart failure or due to hereditary ion channel mutations. It is associated with rapid ventricular activation and impaired mechanical function
Describe the ionic currents that make up an action potential
Sodium and calcium are higher outside than within the cell, while potassium is higher intracellularly
When MP is brought to threshold, rapid transient openings of sodium channels carry the fast sodium current in and cause depolarization. This reduces the permeability of the potassium channel, preventing it at first from removing K+ ions. This depolarization also causes slow calcium channels to open, allowing Ca2+ in. this remains in balance for a plateau phase, before the K_ ion current increase due to fast and slow delayed rectifiers, returning levels to normal
Describe the activation and inactivation gates of the cardiac ion channels
These are gates that may be open or closed depending on the voltage status of the cell.
Eg. fast sodium channels have their gates shut at RMP, but open quickly with depolarization. Inactivation gates are open at rest, but shut as depolarization occurs. This means there is a brief delay between activation and inactivation, so allows a short transient sodium current, and is responsible for the prolonged refractory period of the AP. The gates progressively reset during repolarization
Describe how reentrant arrhythmia occurs
It is due to propagation of a current around a region in which activation is blocked due to refractoriness or injury. If only one side allows propogation, the wave will move around the region of block, and pass retrogradely up the other side. This means it is able to reactivate tissue and generate sustained activation around the entry circuit, if the time of propgation is the same as the effective refractory period of tissue (when reactivation cannot occur).
This means it requires a circuit, a unidirectional block, slow conduction or short ERP, and a trigger.
Vulnerability increases with decreased conduction velocity and refractory periods. In ventricular myocardium, this is most probably when repolarization is not spatially homogeneous
Describe WPW
The bundle of kent is present, proving an accessory pathway for propogation to move between atria and ventricles. Normally, the early activation collides with normal activation via the slower AV node current. This gives a wide QRS with slurred delta wave beginning, and short PR interval
It becomes an issue if ectopic activation occurs in the atria or ventricles which tissue in one of the pathways is refractory. This can cause rapid tachycardia, ventricular fibrillation and death
Describe why conduction velocity is important
The wavelength for a reentrant arrhythmia depends on conduction velocity and effective refractory period. Factors reducing the velocity increase the probability of this. It is influenced by cell dimension, gap junction density, and status of the membrane sodium channels
In the vulnerable period, the myocardium has a medium low MP, meaning few inactivation gates have rest- this means the number of sodium channels able to open is small, giving a slow depolarising current and non-uniform repolarization
What are the three main consequences for cardiac rhythm during ischaemia?
ATP decreases, so sodium potassium ATPase is inhibited, raising K+o and Na+i. This causes
- Slow conduction
- Reduced AP duration with nonuniform repolarization
- After-depolarizations
Describe how myocardial ischaemia causes slow conduction
Increased Extracellular potassium reduces the RMP, inactivating Na+ channels as the gates are partially closed already, and slowing conduction. Acidosis leads to decoupling of gap junctions, increasing electrical resistance and further reducing conduction velocity
Describe how myocardial ischaemia causes reduced AP duration and non-uniform repolarization
Kyperkalaemia reduces AP duration via the rectifier and the APT dependent currents. This reduces AP duration in the ischaemic region, leading to nonuniform current
Describe how ischaemia causes after depolarizations
The reduction of ATP means Ca2+i rises, and spontaneous release of oversoaded SR generates calcium transients, and increased extrusion of Ca2+ via the Na+/Ca2+ exchanger. This generates a depolarizing current. Typically these occur as DADs
Describe how MI may lead to VF
Onset of VT can cause positive feedback, where increased HR increases O2 demand and reduces diastolic perfusion. Increased HR can also impair ventricular performance further, increasing the extent of the ischaemic region and making VF more likely.
Tissue heterogeneity as a result can lead to disordered structure and electrical coupling, allowing a potential reentry arrhythmia to occur
Describe how cardiac rhythm is affected in heart failure
Cellular and structural changes occur, with dilated atria (increasing reentrant path length and stimulating stretch activated ion channels) .
It also causes atrial fibrosis, resulting in region dependent slowing of conduction
Changes in sodium calcium exchangers can also cause DADs and trigger reentrant arrhythmia
There is also remodelling of ANS inputs to the atria in a heterogeneous way, influencing its electrical properties
Similar processes occur in the ventricles
Describe LQTS
Ventricular arrhythmias that are triggered by exertion or emotional excitement, leading to fainting and sudden death
This is due to prolonged APDs, and generation of APs late in the plateau or early in repolarization.
EADs can result from prolonged APs, allowing Ca2+ channels to resent and reactivate. These channels are sensitive to adrenergic stimulation, explaining the reason for the occurrences.
Reentrant arrhythmia is a great risk due to increased non uniformity of repolarization
Describe the causes of LQTS
May be diet or drug induced
- Hypokalaemia
- Amiodarone (prolongs QT interval)
- Hereditary membrane ion channel issues
Describe the three common LQTS hereditary channelopathies
LQT1: Most common, due to mutation in delayed slow K+ rectifier channel, reducing repolarization and increasing APD
LQT2: Mutation of the rapid K+ rectifier channel, increasing APD
LQT3: Mutation in the sodium channel, causing failure to maintain INa inactivation later in the action potential. This allows late inward current, delaying repolarisation and increasing APD
Describe the ECG features of LQTS
A long QT interval
If VT results, it shows continuously varying polymorphic VT, named Torsade de Pointes.
It may resolve spontaneously or progress to VF
What are the equations for cardiac output and stroke volume?
CO = HR x SV SV = EDV - ESV
What overall factors affect ventricular performance?
Preload (Increased preload increases SV)
Afterload (Increased afterload decreases SV)
HR
Inotropic state
How does Calcium affect cardiac muscle contraction
Depolarization opens L type Ca2+ channels in the T tubules, allowing Ca2+ to enter the cell and bind to RyR2 receptors on the SR, opening calcium release channels. Therefore, Ca2+ conc rises rapidly in the cytoplasm.
Ca2+ then binds to regularatory protein TnC, allowing active sites on the thin filaments to be expose and allowing cross bridge formation.
How is Ca2+ removed from the cardiac cells?
SERCA pumps transfer Ca2+ into the SR, where it is stored.
Also some extrusion by Na/Ca exchangers
What factors affect inotropic state of the heart?
Magnitude and rate of SR calcium release
Affinity of TnC for Ca2+ ions
Describe the channels involved with Ca2+ release
The adenylate cyclase system is the most important
Gs stimulates adenylate cyclase, increasing cAMP, more protein kinase A and phosphorylation of L-type Ca2_ channels, phospholamban, ryanodine receptors and TnI. This leads to opening of L type calcium channels, SR stimulation, faster Ca2+ kinetics and faster X bridges
Therefore- faster Ca2+ release and reuptake, increasing inotropy
What does the SNS and PNS do in terms of Ca2+ release in cardiac function?
Noradrenaline and adrenaline act via B1 receptors to cause Gs activation
ACh from the PNS acts on M2 receptors, which activates Gi, which inhibits adenylate cyclase and increases K+ reuptake, shortening APs
Describe how force and length are related in cardiac contraction
There is both passive force and active force.
Passive force is related to the stretch acting on resting muscle, and active is that generated at a given sarcomere length.
Passive force limits sarcomere length to less that 2.4um
The force length relationship is much steeper in cardiac than in non cardiac contraction- this is due to the length dependent affinity of TnC for Ca2+
How does hypoxia affect the contractility of the heart?
If oxygen supply is reduced relative to demand, ATP stores quickly become depleted and pump operation is impaired.
Ca2+ in diastole is therefore elevatd, causing reduced relaxation, impacting electrical function and filling. Acidosis can also set in, impacting mechanical function as H+ competes with Ca2+ for TnC binding.
There is also increased extracellular K+, affecting AP duration, as the speed of depolarization is reduced.
Describe how myocyte orientation affects cardiac contractile function
Myocytes have a principal orientation, defined by the organization of collagen. When the heart beats, most of the pump function is performed by wall thickening, rather than any real change to the diameter of the heart.
How does the heart contract in space during normal systole?
- There is cifcumerential and longitudinal shortening, as well as wall thickening- changes are greatest endocardially
Circumferential shortening is greater than longitudinal.
Some torsion occurs as the apex twists counter-clockwise
Some shear deformations involve movement of cells relative to one another.
This is reversed in diastole
How does heart remodelling in heart disease affect cardiac geometry?
Myocyte hypertrophy and wall thickening
Increased LV collagen density and stiffness
Circumferential and longitudinal shortening decrease
EF is generally mainttained initially by increased torsion
Eventual enlargement of ventricular cavity ad reduction of ejection fraction
Where does cardiac innervation originate from?
Pre-ganglionic sympathetic fibres come from upper thoracic segments of the spinal cord, ascending in the paravertebral chain to synapse with postganglionic neurons in the sup, middle and stellate cervical ganglia.
Preganglionic vagal neurons come from the medulla oblongata and course down the neck and chest as branches of the vagus nerve.
Describe where the different nerves innervate the heart
Parasymp innervation of the SA and AV node, and atrial myocardium, is dense. The ventricles are less densely innervated
Sympathetic innervation is relatively homogenous
The right fibres innervate the SA, while the left do the AV node
How does sympathetic innervation regulate cardiac function?
Through norepi acting on B1 receptors in the myocardium. This causes phosphorylation of If, allowing more Ca2+ in and more reuptake into the SR to shorten AP duration
causes- increased rate
Reduced AP duration, so acceleration of impulse propagation through the AV node
Increased inotropic state
What happens if we stimulate the left vs right stellate ganglion?
Left- it predominantly innervates the AV node so we see less HR change but greater systolic pressure
If we stimulate the RHS it targets the SA node so we see a large change in HR but reduced systolic pressure change.
How does sympathetic stimulation alter the cardiac cycle
Pressure of atrial and LV contractions are increased
Initial blood ejection speed and max ejection speeds are greater
SV increases due to reduced ESV
Filling occurs faster, despite the reduction in diastolic interval
How does the parasympathetic nervous system alter the cardiac cycle?
Mediated by ACh, which binds to M2 receptors to turn off the Gs pathway, increasing K+ extrusion and reducing AP duration
It reduces HR
Also causes deceleration of impulse propagation through the AV node (and may cause block)
Compare and contrast the use of PNS vs SNS to regulate the heart
PNS stimulation is instant, SNS is slower, so respiratory sinus arrest is due to PNS stimulation/ this is because ACh has lots of sites and esterases, unlike epi/norepi
The PNS dominates short term heart rate control, and normally checks resting heart rate. When it’s active, the vagus is turned down
Describe how oxygen supply and demand affect the heart, and the factors that determine myocardial O2 consumption
Interruption to blood supply leads to decline in ventricular performance, with prolonged underperfusion leading to irreversible cell damage. Function is dependent on aerobic metabolism
Determinants include basal mechanism- the metabolic cost of maintaining organelle systems
Wall force development is related to pressure generated and dependent on the geometry of the ventricle- eg. a dilated heart requires more wall force development for a given LV pressure, both in terms of magnitude and time
Also inotropy and heart rate
What factors affect the heart’s oxygen supply?
Aortic pressure, extravascular compression (ie as the heart contracts the vessels get squished) and local regulation
This has impacts on perfusion pressure, impedance, and the need for CaO2, O2 extraction and vessel flow
MVO2 = Q x (CaO2 - CvO2)
Note that there is a capillary for each myocyte!
What determines coronary blood flow?
Coronary blood vessels are compressed during isovolumetric conraction, with some small recovery during systole. It then relaxes and allows full flow. Normally, Diastolic pressure time index should be greater than tension time index, but an loss of health can change this. Vascular resistance is mainly controlled by local factors
The SNS causes vasoconstriction of these vessels, resulting in vasoconstrictor tone under normal situations
It is often overridden by a concurrent increase in oxygen demand during times of stress.
What is the structure of the glomerulus?
The afferent blood supply goes to the glomerulus, which has the glomerular filtration basement- fenestrated endothelium, basement membrane and podocytes. Prourine is produced by fluid’s movement through these layers
What are the key roles of the kidneys?
Elimination of waste products
Control of fluid balance
Regulation of acid-base balance
Production of hormones
How does the kidney perform elimination of waste products?
The rate at which the blood is cleared is defined as the GFR, which is normally >120mL/min
What is the difference between AKI and CKD?
AKI is acute kidney injury, and occurs over hours to days
CKD is chronic kidney disease, and occurs over weeks, months or years. It is progressive but irreversible
Describe AKI and how it is staged
It can have multiple aetiologies, and is assoc with many preventable hospital deaths.
It is defined in 3 stages, with 3 being worse, and assoc with increased risk of death
What are the different types of AKI?
Pre renal
Renal
Post renal
How do you treat AKI?
Identify high risk patients and optimise their care
Stop nephrotoxic agents
Assess and optimise volume status
Monitor creatinine and urine output
What are some categories of patients ‘at risk’ of AKI?
CKD patients Those over 75 HF patients Liver disease CVD DM Polypharmacy
What are some medications that can be nephrotoxic?
NSAIDs
Gentamicin
Anti-hypertensive
Meds that are renally excreted should be revised
How do we assess volume status?
Check for dry mucous membranes
JVP
Oedema
Sunken eyes
What can we investigate in terms of AKI?
Strep serology Antibodies Hepatitis Coagulation Biopsy Ultrasound
How do you diagnose CKD
GFR will be very low- can be measured with Cr clearance or by clearance of injected substances eg. insulin, isotopes
What are some issues with using Cr clearance to determine GFR?
It is secreted in small amounts by the tubules, and so using creatinine tends to overestimate the GFR
Moderate and severe CKD also confounds the interpretation of creatinine clearance. As filtration decreases, extrarenal excretion of creatinine increases and muscle mass decreases, resulting in an overestimation in end-stage patients
What are the categories of GFR and Albumin staging?
5 stages for GFR going from >90, 60, 30, 15 and <15
Albuminuria has 3 stages of <30, <300 and >300
What can cause CKD?
Diabetic nephropathy
Glomerulonephritis
Hypertensive nephrosclerosis
PKD
What secondary factors does CKD engender?
Systemic hypertension Intraglomerular hypertension Glomerular hypertrophy Ca and P Dyslipidaemia Proteinuria Tubulo-interstitial fibrosis Toxicity of iron, ammonia and/or middle molecules
How does hypertension interact with CKD?
Progression of CKD is linked to HT, and lowering it can slow the speed of progression
How does proteinuria affect CKD and how can it be modified?
It’s important for prognostics. Reducing proteinuria improves outcomes
It can be modified with weight loss, ACEi/ARB, statins, moderate protein restrictions, alowering BP
How are calcium and phosphate implicated in kidney disease?
Ca and P content of the kidney is increased in CDK, assoc with progressive decline in renal function. it gets deposited within the kidney, but its reduction can be assoc with reduction in rate of decline
This is managed by limiting dietary phosphate, or giving phosphate binders so that phosphate is not absorbed.
How does water balance change in CKD?
CDK patients are more prone to either dehydration or volume overload.
What other aspects of the kidney are affected in CKD?
Reduced EPO, vitamin D, RAA etc
Issues with Na, P regulation
Typically develops metabolic acidosis due to lack of non-organic acid excretion- may need to add oral sodium bicarbonate
Describe uraemia
Manifestation of organ dysfunction typically seen in CDK 4/5
No single compound is solely responsible
How does uraemia affect the different body systems?
Neuro- fatigue, sleep, headache, seizures, paralysis
Haem- anaemia, easy bleeding, platelet dysfunction, infection
CV- pericarditis, HT, HF, IHD, PVD
Pulmonary- Pleuritis, uraemic lung
GI- anorexia, N&V, bleeds
Metabolic- glucose intolerance, hyperlipidaemia, malnutrition, sex dysfunction, infertility, osteodysplasia
Skin- pigmentation, easy bruising, uraemic frost, pruritis
Psych- depression, anxiety, denial, psychosis
How do you manage uraemia?
Treat the primary disease, secondary factors
Avoid nephrotoxins
Correct abnormalities
Renal replacement therapy
How do you treat end stage kidney disease?
Conservatively if not indicated for other treatment
Dialysis (can be peritoneal or haemodialysis)
Renal transplant (can be cadaveric or living)
Describe the RAAS pathway
Activated by SNS activity, low BP or low Na/K+ passing the JG cells
Causes vasoconstriction, formation of angII, and secretion of aldosterone.
What does the RAAS system do to worsen conditions?
It can increase activity is CCF and hypertension as it works in harmony with the SNS
It’s involved with CHF progression
Can have adverse CV effects including hypertrophy, atherosclerosis development, and pro-inflammatory conditions
Where do agents acting on the RAAS have their effect?
ACEs act on angiotensin converting enzyme, which changes Ang 1 to Ang2. However, blocking this also breaks down bradykinin and increases levels of Ang9 and heptopeptide concentrations increase. This means it has multiple benefits for blood vessels.
However, other pathways can be used instead, to increase Ang II over time
Ang II antagonists- inhibit angiotensin II type 1 receptors
Where does angiotensin II act?
Phospholipase C GPCRs
What are the different ang receptors and what do they do?
Type I receptors- affect the kidney, heart, VSM, Brain, adrenal glands, adipocytes and placenta. Main target of ARBs
Type II receptors- affect the heart, adrenals, CNS, kidneys Also counterbalance some type I effects and cause cell proliferation & apoptosis. These are allowed to exert their beneficial effects when type I receptors are blocked
What are the pathophysiological effects of angiotensin II?
Cardiac myocytes: Cause hypertrophy, apoptosis, cell sliding, wall stress, increased O2 consumption and impaired relaxation
Fibrobasts: Cause hyperplasia, collagen synthesis and fibrosis
Peripheral artery: Cause vasoconstriction, endothelial dysfunction, hypertrophy and decreased compliance
Coronary artery: Cause vasoconstriction, endothelial dysfunction atherosclerosis, and thrombosis.
What does aldosterone do?
Causes hypertrophy and Ne in cardiac myocytes
Hyperplasia, collagen synthesis, fibrosis in fibroblasts
Vasocnstriction, endothelial dysfunction, hypertrophy and decreased compliance in peripheral arteries
Potassium loss and sodium retention in the kidney
What are the benefits of ACEi initially and a few weeks later?
Benefits are reduced ang II concentration, reduced aldosterone concentration, and potentially increased Ang 9. Also, bradykinin levels rise, causing vasorelaxation and increased endothelial function
However, eventually aII and also begin to increase, due to chymase activity
What are the drug names used in RAAS, and their pharmacokinetics?
Ace inhibitors are most common, especially cilazapril. All others end in ‘pril’
ARBs include candesartan. All others end in sartan
ACEs are given as prodrugs and hydrolysed int he liver. They are excreted mostly renally
ARBs have variable excretion
What do ACEis and ARBs do?
They cause vasodilation, lowering arterial and venous pressure, and reducing preload and afterload
They decrease blood volume, causing natriuresis an diuresis.
Decrease sympathetic activity
Decrease cardiac and vascular hypertrophy
What are the indications for ACEis and ARBs?
ACEs: Hypertension, either monotheraphy or combination with a diuretic
Also CCF as part of multiple treatments with a diuretic, B blocker or aldosterone antagonist
ARBs: Used in ACE inhibitor intolerant patients, hypertension and heart failure
NEVER USE THE TWO TOGETHER
What are the side effects from ACEis and ARBs?
ACE: Produce a dry cough due to bradykinin increases, as well as hyperkalaemia, decreasd renal function (initial), hypotension and angioedema due to vasodilation
ARBs show dry cough in small amount of people, hyperkalaemia, renal deterioration, hypotension and angioedema, though less than ACEis
They are both contraindicated in pregnancy
When do we need to be careful when using ACEis and ARBs?
In hyperkalemic patients
Renally impaired patients
Volume depeted or diurised patients, as they are dependent on RAAS to overcome their dehydration
What are absolute contraindications in the use of ARBs and ACEIs?
Pregnancy
Bilateral renal artery stenosis, as they have narrowing proximal to the glomerulus
They need ang II to constrict the efferent arteriole to maintain glomerular pressure.
If it is not present, it can reduce perfusion across the glomerulus and cause AKI. Therefore, you need to watch creatinine for the first few weeks when going on the drug.
What are some future direction in ARBs and ACEis?
Can get renin inhibitors potentially
Also vasopeptidase inhibitors which block the breakdown of ‘good’ things like bradykinin and substance P.
What are the functions of alpha receptors?
A1 (post-synaptic): They cause vasoconstriction and increase BP (A1a in the prostate)
A2 (pre and post synaptic): Inhibit release of norepi and insulin
What do alpha blockers do?
They act on alpha 1 receptors to block noradrenaline landing (alpha 2 antagonism isn’t used clinically)
What are some examples of alpha blockers?
Doxazosin- blocks all a1 subtypes for causing vasodilation
Tamsulosin- specific to a1a so useful for prostatic profile but with little effect on BP
