The Cardiovascular system

Session 1Diffusion is affected by:

The area available for exchange The difficulty of movement through the barrier. The concentration gradient.

Capillaries are the site of diffusion and they are composed of single layer endothelial cells surrounded by basal lamina.

Small hydrophilic substances such as glucose diffuse through aqueous pores between endothelial cells. Other substances such as O2 and CO2 are lipophilic and diffuse through the membrane.

Capillary density –The more metabolically active the tissue the more capillary dense it is. Generally area is not the limiting factor.

Diffusion resistance – Resistance to diffusion depends on the nature of the barrier, the nature of the molecules which are diffusing and the path length. Path is shortest in most active tissues.

Concentration gradient - This gradient does depend on the concentration of substances in the blood entering the tissue, but the more important variable is the flow of blood through the capillary. Unless blood is supplied at an appropriate rate, the gradients driving exchange will dissipate, and nutrients will not be supplied at the right rate.

Therefore maintaining the right flow of blood (perfusion rate) for the prevailing level of metabolic activity is the most critic thing.

Tissue Minimum blood flow (ml/min)

Maximum blood flow (ml/min)

Brain – extremely intolerant of flow interruption

750 750

Heart – also intolerant 300 (rest) 1200 (extreme work)Kidney: high constant flow 1200 1200Gut: depends on ingestion 1400 2400Skeletal muscle 1000 16000Skin – not very metabolic 200 2500Other 200 200Total 5050 24250

So the CVS must supply between 5-25 l.min-1 of blood to the tissues whilst at all times maintain perfusion to vital organs such as the brain, heart and kidneys.

Regulating blood flow

If a pump is just connected to a network of vessels blood will only flow to the parts that are easiest to perfuse.

The brain is harder to perfuse due to gravity To regulate blood flow you need to add resistance to the system

Reduce the ease with some regions are perfused in order to direct blood flow to the areas harder to perfuse to.

Arterioles are the resistance vessels The total flow in the system has to be able to change. This occurs because the veins act as a

store of blood due to their ability to collapse or distend.

Structure of Blood vessels

Elastic Arteries permit elastic recoil of vessel. Ensure blood flow during diastole

Muscular Arteries Blood flow requirements vary. Control flow to large areas e.g. Femoral to leg

Arterioles diameters are small, any change in diameter has a great effect on peripheral resistance. Increased peripheral resistance leads increased blood pressure. Some treatments for hypertension use drugs which cause relaxation of arteriolar smooth muscle.

The diameter of the muscular arteries and arterioles is controlled by the ANS. The arterioles branch into smaller vessels (metarterioles), which carry blood into the smallest vessels in the body, the capillaries.

Capillaries

1 cell thick

The capillary wall may be continuous or fenestrated. Both these types of the capillaries may be surrounded partially by pericytes.

In addition to these two types of capillaries, there is a category of vessels found in the liver, spleen and the bone marrow, called sinusoids, which are generally large in diameter and may contain special lining cells and an incomplete basal lamina. Under certain conditions, some blood cells leave the circulatory system to enter the tissue spaces.

Venules and veins

Capillaries merge into large vessels called the venules which merge to form the veins. The construction of a vein is essentially similar to that of an artery; expect that its wall is thinner and its lumen wider and irregular. The veins usually contain semilunar paired valves

that permit blood to flow in only one direction; those veins are narrower than 1 mm in diameter and those in the thoracic and abdominal cavities do not have valves.

The veins collapse if blood pressure is not maintained; the blood flow in arteries is the result of cardiac systolic pressure, whereas blood flow in veins, to a great extent, determined by the “muscle-pump” action in the leg and pressure factors in the abdominal and the thoracic cavities.

Avascular structures include cartilage, epithelia, cornea and some others.

Arteriovenous shunts

It is the passage of blood directly from arteries taken, without going through the capillary network. This is achieved by direct passage through the channels and the contraction of the pre-capillary sphincters.

Blood system blood supply

The vessels are called vasa vesorem that supply the larger blood vessels walls with blood. There purpose: They help warm the blood in those veins and supply nutrients to the vessel wall.

Vena comitantes

They are an irregular branching network of veins surrounding and accompanying deep arteries. This arrangement serves as a counter current heat exchanger between warm arteries and cold blood in the peripheral veins. The veins produce a vascular sheath around the arteries as a result they are stretches and flattened as the artery contracts which aids moving venous blood.

Varicose veins

A thrombosis occurs which occlude the vein therefore blood drainage back to the heart is occluded. Weakened veins dilate under the pressure of supporting the blood against gravity, this affect is pronounced in this condition. Heart Muscle

Involuntary yet striated, contracts rhythmically and automatically

Elongated nuclei (1 or 2 per cell) lie deep in the fibre. Fibres may bifurcate and form connections giving a complex 3d network. The cells are joined end to end by intercalated discs.

Sarcoplasmic reticulum has no terminal cisterna.

The muscle fibres branch and anastomose.

Session 2 and 3The heart as a pump

The heart is two pumps in series. Thin walled atria act as reservoirs to supply muscular pumping chambers – the ventricles. In flow and out-flow to the ventricles are separated by valves. The right

side of the heart pumps blood to the lungs (pulmonary circulation), the left side to the body – or systemic circulation.

Cardiac Muscle

The myocardium consists of individual cells joined by low electrical resistance connections. Cells contract when action potential in membrane. The action potential causes a rise in intracellular [Ca2+]. The AP is long – a single contraction lasts 280ms – systole. Action potentials triggered by spread of excitation from cell to cell, so to each heart bear all the cells in the heart normally contract.

Pacemakers

In the normal heart the pacemaker in sino-atrial node - right atrium. Activity first spreads over the atria - atrial systole to reach the atrio-ventricular node, where delayed for about 120 ms.

Then from a-v node spreads down the septum between the ventricles. This then spreads through the ventricular myocardium from inner (endocardial) to outer (epicardial) surface

Thus the ventricle contracts from the apex up, forces blood towards the outflow valves.

Contraction of the atria is not forceful, but the ventricular muscle is organised into figure of eight bands which squeeze the ventricular chamber forcefully in a way most effective for ejection through the out flow valve. The apex of the heart contracts first and relaxes last to prevent back flow.

The Cardiac Cycle

It is the sequence of pressure flow changes and valve operations that occur with each heartbeat.

At rest the SA node generates an AP about once a second (60bpm). This produces a short atrial systole followed by a longer ventricular systole, ventricular systole lasts about 280ms. This is followed by a relaxation lasting about 700ms before the next systole.

As the ventricular muscle relaxes, the intra-ventricular pressure falls, and the atrio-ventricular valves (tricuspid and mitral) open as atrial pressure exceeds ventricular. The atria have been distended by continuing venous return during the preceding systole, so initially blood is forced rapidly from the atria into the ventricles – the rapid filling phase. Filling of the ventricles continue throughout diastole, at a steadily decreasing rate until the intra-ventricular pressure rises to match atrial pressure. At low heart rates the ventricles are more or less full before the next systole begins.

Systole begins with atrial systole – contraction of the atria, which forces a small extra amount of blood into the ventricles. After a delay of about 100-150ms the ventricles being to contract. As intra ventricular pressure rises, so blood tends to flow the ‘wrong way’ through the A/V vales, producing a turbulence which closes the valves forcible. The ventricles then contract ‘isovolumetrically’ and the intra ventricular pressure rises rapidly until it exceeds the diastolic pressure in the arteries, when the outflow valves open. There is then a period of rapid ejection of blood, and both intra ventricular and arterial pressure rise to a maximum. Towards the end of systole intra ventricular pressure falls, and once it is below the arterial pressure the outflow valves close, and when the atrial pressure is reached the A/V valves open, and the whole process starts again.

Heart sounds

In the normal heart there are always two sounds. Two others may be audible

first sound - ‘lup’ - closure of a/v valves – onset of ventricular systole second sound - ‘dup’- closure of outflow valves – end of ventricular systole So roughly 280ms between lup and dup. Then interval of 700ms. It can be normal to hear two more sounds. The third sound may be heard early in diastole,

and a 4th sometimes associated with atrial contraction.

Quality of sounds may change if valves altered.

Sounds may split if valves of right and left heart do not close at same time.

Murmurs - turbulent blood flow generates murmurs

Aortic valve - 2nd intercostal space, right sternal edge

Pulmonary valve - 2nd intercostal space, left sternal edge

Tricuspid valve - 4th intercostal space, left sternal edge

Mitral valve - 5th intercostal space, mid-clavicular line

Narrowed valve – stenosis

Valve not closing properly – incompetence.

Also during exercise in normal individuals turbulent flow can occur and generate murmurs.

Cardiac Output = Stroke Volume X heart rate. (at rest 80ml X 60 = 5l.min-1)

Heart Development

Cephalocaudal folding brings heart into thoracic region, lateral folding creates heart tube. Paired endocardial tubes fuse to create primitive heart tube. This tube receives venous drainage from its caudal pole and beginning to pump blood out the 1st aortic arch into the dorsal aorta.

At this time the heart tube is suspended in the pericardial cavity by a membrane that subsequently degenerates.

The heart tube continues to elongate and bend on day 23. This bending, due to cell shape changes, creates the cardiac loop and is completed by day 28.

Cephalic portion – Bends ventrally, caudally & to the right

Caudal portion - Bends dorsally, cranially & to the left

Looping occurs because it puts:

Primordium of right ventricle closest to outflow tract

Primordium of left ventricle closest to inflow tract

Atrium dorsal to bulbus cordis, i.e. inflow is dorsal to outflow

NB: Primordium - the first recognizable, histologically differentiated stage in the development of an organ.

After looping, the atrium communicates with ventricle via atrioventricular canal

Development of the sinus venosus

In the middle of the 4th week, the sinus venosus receives venous blood from the right and left sinus horns.

Initially both horns are equal in size, venous return shifts to right side, Left sinus horn recedes. Then right sinus horn is absorbed by enlarging right atrium.

Development of the atria

Right atrium develops from most of the primitive atrium, the sinus venosus and it receives venous drainage from the body and the coronary sinus.

Left atrium develops from a small portion of the primitive atrium, absorbs proximal parts of the pulmonary veins and receives oxygenated blood from the lungs.

Foetal circulation

Lungs are non-functional Receives oxygenated blood from

mother via placenta and umbilical vein

By-passes the lungs (ductus arteriosus)

Returns to the placenta via umbilical arteries

BUT -the change in circulation must happen immediately.

By-pass the liver (ductus venosus) – this stops it stealing all the oxygenated blood.

Early arterial system begins as a bilaterally symmetrical system of arched vessels. These undergo extensive remodelling to create the major arteries leaving the heart.

4th arch – Right becomes the Right subclavian artery, Left becomes the aortic arch6th arch – Right becomes the right pulmonary artery, Left becomes left pulmonary artery and ductus arteriosus.Septation (day 27 – 37)

Once the primitive heart tube has looped, the most complex sequence of heart development gets underway to create the “two pumps in series” configuration required. Therefore in the process of septation the primitive heart tube becomes divided into chambers and the outflow tract is subdivided into pulmonary trunk and aorta.

It starts by endocardial cushions developing in the atrioventricular region; this divides the developing heart into right and left channels.

Atrial septation

Division of the common atrium involves the formation of two septa with 3 holes. Septum primum grows down towards the fused endocardial cushions. The ostium primum is the hole present before the septum primum fuses with the endocardial cushions. Before ostium primum closes, a second hole, the ostium secundum appears in the septum primum. Finally a second crescent shaped septum, the septum secundum grows; the hole in the septum secundum is the foramen ovale. The two holes not lining up allow it to be closed at birth. The fossa ovalis is the adult remnant of the shunt used in utero to by-pass the lungs.

Ventricular septation

Ventricular septum has two components, the muscular and membranous.

The muscular portion forms most of the septum and grows upwards towards the fused endocardial cushions. This leaves the 1o interventricular foramen.

The membranous portion of the interventricular septum formed by connective tissue is derived from endocardial cushions to fill the gap.

Endocardial cushions also appear in the truncus arteriosus; form a spiral septum between aorta and pulmonary trunk.

At birth – the change in circulation must happen immediately.

Respiration begins, left atrial pressure increases and foramen ovale closes (septum primum pushed against septum secundum) and ductus arteriosus contracts. Placental support removed and ductus venosus closes.

Congenital heart defectsAetiology – The cause of a specific disease.

Can be due to genetic e.g. – down’s, turner’s, Marfan’s syndrome

Or Environmental – teratogenicity from drugs, alcohol etc.

Or maternal infections – rubella, toxoplasmosis etc.

Classification

Acyanotico Left to right shunts: atrial septal defects, ventricular SD, patent ductus arteriosus o Obstructive lesions: Aortic stenosis, pulmonary stenosis, coarctation of the aorta

(narrowing of aorta where ductus arteriosus inserts), mitral stenosis. Cyanotic (complex right to left shunts)

o Tetralogy of Fallot – pulmonary stenosis, ventricular septal defect, right ventricular hypertrophy, over-riding aorta.

o Transposition of the great arteries – RV connected to aorta, LV connected to pulmonary artery, not viable unless a-v shunt or ductal shunts present.

o Total anomalous pulmonary venous drainageo Univentricular heart – single ventricle.

Session 4The Autonomic nervous system

It is important for regulating many physiological functions, it is largely outside voluntary control and it acts on smooth muscle, exocrine secretion and lastly the rate and force of contraction in the heart. The defining characteristic of the ANS is that one nerve cell in the pathway is located entirely outside of the CNS. The cell bodies of these neurones are located in the structures known as ganglia.

2 divisions the parasympathetic and sympathetic.

Parasympathetic division Sympathetic division Craniosacral origin Thoracolumbar originPreganglionic fibres travel in cranial nerves (3, 7, 9 and 10 or sacral outflow from S2-4

Preganglionic neurones arise from segments T1 to L2 (or L3)

Synapse with neurones in ganglia close to the target tissue

Most synapse with postganglionic neurones in the paravertebral chain of ganglia

Short postganglionic neurones Some synapse in a number of prevertebral ganglia – coeliac, superior mesenteric, inferior mesenteric ganglia

long pre-ganglionic, short post-ganglionic nerves

Short pre-ganglionic, long post-ganglionic nerves. Cell-bodies in lateral horn of the grey matter of spinal cord

Note that in the PNS some ganglia in the neck and abdomen are located further away from the target organs. AND some ganglia in the neck and abdomen of the SNS have longer pre-ganglionic fibres.

Most organs are innervated by the sympathetic NS, rather fewer by the parasympathetic. Some organs have both sympathetic and parasympathetic innervation which generally, but not always, have opposing actions.

Chemical transmitters in the ANSPreganglionic neurones of both divisions release acetylcholine. Ach acts on nicotinic Ach receptors on the postganglionic cell. Nicotinic Ach receptors have an ion channel. Receptors are categorised into types by their responses to different agonists and antagonists.

Postganglionic sympathetic neurones are usually noradrenergic. Different effector organs have different receptor types for NA. There are two broad types α and β receptors, but each is subdivided in their responses to different drugs.

Postganglionic parasympathetic neurones are usually cholinergic. – They usually act on a different type of receptor on the effector cell – the muscarinic sub type

The exception is sympathetic innervation of the sweat glands; here postganglionic neurones release Ach which acts on muscarinic Ach receptors.

All adrenoreceptors are G protein-coupled receptors so have no integral ion channel.

Chromaffin cells of the adrenal medulla are like specialised postganglionic sympathetic neurones. As they release adrenaline which circulates in the blood stream.

NANC non-adrenergic, non-cholinergic – these are other transmitters in the ANS. NANC transmitters are often co-released with either Ach or NA. Examples include, ATP 5-hydroxtryptamine (serotonin), nitric oxide and several neuropeptides including neuropeptides Y; vasoactive intestinal peptide and substance P.

Neurotransmission1. Uptake of precursor2. Synthesis of transmitter3. Vesicular storage of transmitter4. Degradation of transmitter5. Depolarisation by propagated AP.6. Influx of Ca2+ in response to depolarisation7. Exocytotic release of transmitter8. Diffusion to post-synaptic receptors9. Interaction with receptors10. Inactivation of transmitter11. Re-uptake of transmitter or degradation product12. Interaction with pre-synaptic membrane.

Cholinergic transmission

Ach is synthesised by choline acetyltransferase from choline and acetyl CoA in cytoplasm. Some is degraded by cytoplasmic cholinesterase majority is transported into synaptic vesicles by an indirect active transport mechanism. Released by Ca2+- mediated exocytosis. When in synapse interacted with pre- and post synaptic cholinoceptors. But rapidly degraded by cholinesterase. Faster at fast (nicotinic) synapses limiting the synaptic cleft half left of Ach to a few milliseconds. Most choline is recaptured by a choline transporter present in the synaptic terminal.

Drugs: main drug action with cholinoceptors, but can use cholinesterase inhibitors to decrease the rate of Ach degradation and so prolong the lifetime of Ach within the synaptic cleft.

Nicotinic cholinoceptors antagonists may have a preferential ganglion or neuromuscular blocking action. Rarely used, but neuromuscular used to cause muscle paralysis during anaesthesia.

Muscarinic cholinoceptors agonists vary in their muscarinic nicotinic selectivity and resistance to degradation by cholinesterase. No significant selectivity between M1, M2, M3, receptors. Clinical use glaucoma.

Muscarinic cholinoceptors antagonists – again little selectivity but variety in peripheral and central actions. Hyoscine used as anaesthetic premedication decreases bronchial and salivary secretions, prevents reflex bronchoconstriction. Also pupillary dilatation and paralysis of accommodation can be caused by muscarinic cholinoceptors antagonists.

Cholinesterase inhibitors – differ in their longevity of action and their peripheral versus central effects. They are used to acutely reverse the effects of non-depolarizing neuromuscular blocking agents used in anaesthesia, glaucoma and in myasthenia gravis.

Adrenergic Transmission

Noradrenaline release is triggered by depolarization of the nerve terminal membrane, Ca2+ entry and fusion of vesicles with the pre-synaptic plasma membrane. Released noradrenaline can interact with both pre and post adrenoceptors. However, the opportunity to interact with receptors is limited by a high affinity re uptake system (Uptake 1). Any NA escaping from the synaptic cleft is removed from the extracellular space by another, widespread, lower affinity re-uptake system called uptake 2. It is either re-used or broken down by monoamine oxidase.

Drugs

α-methyl-tyrosine – competitively inhibits tyrosine hydroxylase, so blocks synthesis of NA. Only use in pheochromocytoma.

Α-methyl- DOPA – is taken up by adrenergic neurones and is converted to α-methyl- noradrenaline. Unlike NA, α-methyl-DOPA is poorly metabolized and therefore accumulates in the synaptic vesicles of noradrenergic terminals. It is released by Ca2+-mediated exocytosis, but it preferentially activates pre synaptic α2-adrenoceptors reducing transmitter release. Treatment hypertension.

Adrenergic blocking drugs – (e.g. guanethidine) block action on reuptake of neurotransmitter, and cause depletion of NA from synaptic vesicles. Rarely used.

Adrenoceptor agonist – highly selective receptor subtypes have been made. o β1 agonists – cause positive inotropic and chronotrophic effects. But cause cardiac

arrhythmias.o β2 agonists – reverse bronchoconstriction in asthmatics (salbutamol).o α1 agonists – nasal decongestants.o α2 agonists – are anti-hypertensive.

Adrenoceptor antagonistso α-adrenoceptor antagonists are used to cause peripheral vasodilatation in the

treatment of peripheralvascular disease. Not used in hypertension because they cause postural hypotension and tachycardia

o β- adrenoceptor antagonists (beta blockers) used to treat hypertension, cardiac arrhythmias, angina and MI. Possible side-effects include brochoconstriction, bradycardia, cold extremities, insomnia and depression.

Functions of the ANS Regulates physiological functions Sympathetic activity is increased under stress Parasympathetic system is more dominant under basal conditions They both work together to maintain balance

Organ Action of sympathetic

Receptor Action of parasympathetic

Receptor

Pupil of the eye Dilation 1α Contraction of sphincter muscle

M3

Salivary gland secretion becomes more viscous (amylase)

1 α β secretion becomes more watery

M3

Airway of the lung

Relax 2β Contract M3

Heart- SAN Increase rate 1β decrease rate M2Heart – atrial muscles

Increase force of contraction

1β Force decrease M2

Heart – ventricular muscle

Increases force and automaticity*

1β No effect M2

Blood vessels in most tissues

Constriction α no effect -

Organ Action of sympathetic

Receptor Action of parasympathetic

Receptor

Blood vessels in skeletal muscle

Dilation 2β No effect -

Blood vessels in erectile tissue

Constriction α Dilation M3

Gut- secretion No effect - Secretion M3Gut- motility Decreases 1 2 2α α β Increases M3Gut – sphincters Constrict 2 2α β Dilation, secretion M3Adipose Tissue Increased

Lipolysis3β storage -

Liver Glycogenolysis, gluconeogenesis

1 2α β No effect

Kidney Renin secretion 1β No effectSweat Glands Secretion M, 1α No effectSweat Glands (palms of hand)

Localised secretion

1α No effect

Male Sex organs Ejaculation α Erection M3

*cardiac automaticity the ability of the cardiac muscles to depolarize spontaneously

Sympathetic drive to different tissues is independently regulated.

Control of the Cardiovascular SystemIt controls, heart rate, force of contraction and peripheral resistance.

Blood Vessels

The smooth muscle in the walls of arteries, arterioles and veins is innervated by the sympathetic Ns. Except in specialised vessels, sympathetic activity causes vasoconstriction. There is constant activity in the sympathetic NS the sympathetic vasomotor tone tending to make arteriolar smooth muscle contract. The tone varies from organ to organ, as does the magnitude of its effect. In skin, for example, vasomotor tone is high, so arterioles, pre-capillary sphincters and arterio-venous anastomosis are generally shut down. Variation in sympathetic outflow produces large changes in skin blood flow, usually for purposes of thermoregulation.

Vasodilation occurs with less sympathetic output

Vasomotor tone occurs with normal sympathetic output

Vasoconstriction occurs with increases sympathetic output

Most arteries and veins have α1-adrenoreceptos – but coronary and skeletal muscle vasculatures also have β2-receptors.

In skeletal muscles vasomotor tone is high at rest, but in exercise is antagonised both by local release of vasodilator metabolites and by specialised vasodilator nervous activity.

Smooth muscle

Activating β2 adrenoreceptors causes vasodilation increases cAMP ® opens a type of potassium channel ® relaxation of smooth muscle

Activating α1 adrenoreceptors causes vasoconstriction increase in [Ca2+]in from stores and via influx of extracellular Ca2+ ® contraction of smooth

muscle

Local metabolites – active tissue produces more metabolites. Local increases in metabolites have a strong vasodilator effect. So it is more important for ensuring adequate perfusion of skeletal and coronary muscle than activation of β2-receptors.

On the other hand the circulation to the brain is virtually unaffected by sympathetic activity.

Sympathetic outflow to blood vessels is controlled from the hindbrain – via the vasomotor centres in the medulla oblongata

Sympathetic activity also produces veno-constriction which is contraction of smooth muscle in the walls of veins. This tends to increase venous pressure and force more blood back towards the heart.

The parasympathetic NS acts only on specialised blood vessels, though its stimulating action on organs such as the guy is associated with the release of mediators which may produce dramatic vasodilatation.

The Heart

Parasympathetic activity tends to slow the heart rate. In the absence of any autonomic activity the heart rate is about 100 bpm, so the normal resting heart rate of about 30 is produced by a constant parasympathetic tone. Initially increases in heart rate are brought about by reducing parasympathetic activity. It acts on M2 receptors, they have a negative chronotrophic effect and it decreases AV node conduction velocity. The synapse with postganglionic cells is on the epicardial surface or within walls of heart at SA and AV nodes.

Rises in heart rate beyond 100 bpm are brought about by sympathetic stimulation. Both parasympathetic and sympathetic outflow to the heart is controlled by centres in the medulla oblongata which themselves receive information from sensory receptors detecting blood pressure (‘baroreceptors’). The postganglionic fibres arrive from the sympathetic trunk, they innervate SAN, AVN and myocardium, release NA and this acts on β1 adrenoreceptors. This acts to increase heart rate (positive chronotrophic effect) and the force of contraction (positive inotropic effect).

The force of contraction of heart muscle – contractility – is increased by sympathetic activity.

The action of the parasympathetic system on heart rate is mediated via Ach acting on muscarinic receptors.

The action of the sympathetic system on heart rate and contractility is mediated via NA acting on β1 receptors. Adrenaline also acts on the heart. The ANS therefore provides the central nervous centres responsible for controlling the CVS with the mean to affect the total peripheral resistance and distribution of blood flow, and the cardiac output.

The heart pacemaker

Cells in the SAN steadily depolarise toward threshold. It is a slow depolarising pacemaker potential; it turns on a slow Na+ conductance and opens Ca2+ channels.

Sympathetic activity increase slope. Parasympathetic activity decreases slope of the pacemaker potential.

Action of noradrenaline

NA acting on β1 receptors in myocardium causes and increase in cAMP phosphorylation of Ca2+ channels increased Ca2+ entry during AP increased force of contraction also increased uptake of Ca2+ in sarcoplasmic reticulum

Drugs acting on the ANSSympathomimetics – α and β – adrenoceptor agonists

CVS uses

Administration of adrenaline to restore function in cardiac arrest and for anaphylactic shock

Β1 agonist – dobutamine may be given in cardiogenic shock

Adrenoceptor antagonists

α adrenoreceptor antagonists – anti-hypertensive agent as inhibits NA action on vascular smooth muscle α1 receptors – vasodilation

β-adrenoreceptor antagonists (beta blockers) – Propanolol – slows heart rate and reduces force of contraction (β1) but also acts on bronchial smooth muscle (β2) brochoconstriction.

Cholinergics

Muscarinic agonists – used in treatment of glaucoma – as it activates constrictor papillae muscle

Muscarinic antagonists – increases heart rate, bronchial dilation, also used to dilate pupils for examination of the eye.

Session 5 – Blood FlowFlow: the volume of fluid passing a given point per unit time

Velocity: the rate of movement of fluid particles along the tube.

Flow α pressure difference between the ends of the vessel.

The flow for a given pressure gradient is determined by the resistance of the vessel.

Flow is the same at all points along a vessel. Velocity can vary along the length if the radius of the rube changes.

If flow constant then velocity α (surface area)-1

Vessels with small cross sectional area have a high velocity e.g. aorta

Vessels with large overall cross sectional area have a low velocity e.g. capillaries.

Types of Flow

Laminar – velocity highest in the centre, fluid on the edge is stationary Turbulent – flow resistance greatly increased

ViscosityThe mean velocity depends on two factors. Firstly, the viscosity of the fluid and secondly the radius

of the tube.

Definition: The property of a fluid that resists the force tending to cause the fluid to flow.

The higher the viscosity the low the mean velocity

Viscosity determines the slope of the gradient of velocity. At a constant gradient, the wider the tube the faster the middle layers move, so:

Mean velocity α cross sectional area of the tube.

Poiseulles Law: ∆ P=Flow×velocity×8×lengthπ r4

P is pressure difference. Therefore resistance increases as viscosity increases, and resistance decreases with the fourth power of the radius.

Connected blood vessels (like electricity.)

R1 R2

Series

R=R1+R2

Parallel

R1

R2

R=(R1xR2)/(R1+R2)

If flow is fixed – the higher the resistance the greater the pressure change from one end fo the vessel to the other

If pressure is fixed – the higher the resistance the lower the flow

The Whole Circulation Flow is constant Arteries are low resistance Arterioles are high resistance Individually capillaries are high resistance but collectively low as many in parallel. Venules and veins are low resistance The pressure within the arteries is high because of the high resistance of the arterioles For a given total flow, the higher the resistance of the arterioles, the higher the arterial

pressure. Therefore if the heart pumps more blood and the resistance for the arterioles remains the

same – the arterial pressure will rise.

Distensible vessels

Blood vessels have distensible walls. As the vessel stretches, so resistance falls. As the pressure within a distensible vessel falls eventually collapse and blood flows ceases before the driving pressure falls to zero.

Distensible vessels store blood, veins are most distensible.

Cardiac Output

Arterial pressure must rise high enough to drive the cardiac output through the resistance of the arterioles. If arteries had rigid walls pressure would rise enough in systole to force the whole stroke volume through the total peripheral resistance and then fall to zero in diastole. This doesn’t happen because arteries stretch, more blood flows in than out, so pressure does not rise so much. As arteries recoil in diastole, flow continues through the arterioles.

Typical blood pressure: 120mmHg/80mmHg

Pulse pressure 40mmHg the difference.

Average pressure calculated as diastolic plus one third of pulse pressure, because systole is shorter than diastole (95mmHg)

Reactive hyperaemia – if the circulation to, say an arm is cut off for a minute or two, then blood flow is restored, there is a massive increase in the arm for a short while. This occurs because when there is no blood flow, metabolites accumulate, so arterioles dilate maximally and when flow is retuned, resistance is very low. Therefore, crucially, flow is very high. Then as high flow washes away the metabolites, the smooth muscle constricts again.

Simply – more metabolism, more blood flow.

Autoregulation – If supply pressure changes, blood flow to a tissue will change. This then changes the metabolite concentration and alters the resistance of arterioles so blood flow returns to an appropriate level for metabolism.

Provided supply pressure remains within certain limits tissues will automatically take what blood they need. If all the tissues in the body alter the resistance of their arterioles to match metabolism then, total peripheral resistance will be inversely proportional to the body’s need for blood flow.

Summary

Arterial pressure must be high enough to ensure tissues get what blood they need, as total peripheral resistance falls more blood is needed. Lastly, central venous pressure fills the heart with every beat.

Session 6 – Control of the CVSThe pumping action of the heart removes blood from the veins, and so tends to lower venous pressure. The blood is pumped into the arteries, tending to elevate arterial pressure. All other things being equal, the more the heart pumps the lower the venous pressure will be, and the higher arterial pressure will be.

Situations

TPR Cardiac output Arterial pressure Venous pressure↓ = ↓ ↑↑ = ↑ ↓= ↑ ↑ ↓= ↓ ↓ ↑

TPR is inversely proportional to the body’s need for blood. If metabolism changes TPR will change and generate ‘signals’ in the form of changes in arterial and venous pressure.

If the body needs more blood, the heart needs to pump more to meet the demand.

This will be achieved if the heart responds to rises in venous pressure and falls in arterial pressure by increasing it output.

Factors affecting Cardiac Output

The cardiac output is the product of stroke volume and heart rate.

Ventricular filling

In diastole the ventricle is isolated from the arteries, and connected to the veins, the ventricle fills until the walls stretch enough to produce an interventricular pressure equal to venous pressure. Within limits, the higher the venous pressure, the more the ventricle will fill in diastole.

The greater the end diastolic volume the harder the ventricle contracts, this is starlings law.

The harder it contracts the bigger the stroke volume.

Subsequently, end systolic volume increases if venous pressure increases.

End systolic volume depends on, how hard it contracts and how hard it is to eject blood.

Force of contraction is determined by end diastolic volume and contractility, contractility is increased b sympathetic activity.

The harder it is to eject blood the higher the pressure rises in the arteries.

Stroke volume will rise if... venous pressure rises or... arterial pressure falls

Control of Heart Rate

Sympathetic activity increases heart rate, parasympathetic decreases it.

The main factor influencing autonomic control of the heart is the activity of baroreceptors which monitor arterial pressure. Stretch receptors in the walls of the aorta and the carotid sinus. This information is released to the medulla in the brain, where collections of neurones – modify the behaviours of the heart and circulation via the ANS. Falls in arterial pressure lead to rises in heart rate and contractility.

Baroreceptors ensure that if arterial pressure falls both heart rate and stroke volume tend to rise.

There is also a minor effect of venous pressure on heart rate – if venous pressure rises, then heart rate rises (also know as the Bainbridge reflex).

How the above applies to real stuffEating a meal – causes increased activity of the gut leads to local vasodilation. So TPR falls, venous pressure rises and arterial pressure subsequently falls.

Continuing that, the rise in venous pressure causes a rise in cardiac output, so fall in arterial pressure triggers rise in heart rate and so cardiac output. Venous pressure reduced by extra pumping of the heart, so arterial pressure also increases so the demand on the system is therefore met.

Changes in heart rate alone – If HR increases with no other change initially CO will tend to rise, but TPR the same. So rise in CO reduces venous pressure so stroke volume falls and cardiac output resumes to original value.

So we can conclude the heart cannot drive the circulation it is driven by it.

Exercise causes, obviously, a massive increase in demand and ‘muscle pumping’ which forces blood back to the heart. With no other changes venous pressure would rise greatly and arterial pressure would fall greatly. The great increase in venous pressure is the main problem as this tends to overfill the heart, i.e. pushes the ventricles onto the flat part of the Starling curve. So there is a risk of pulmonary oedema because the outputs of the right and left ventricles cannot be matched.

Both sides beat at the same rate so can only match by matching stroke volume which relies on the Starling curve. If the right heart pumps more, the left fills more, and so pumps more, but if on the top of the curve the left heart cannot respond to the right so blood accumulates in the lungs. Overfilling of the ventricles is prevented by a rise in heart rate which occurs as exercise begins this is driven by the brain. So when the venous pressure starts to rise, heart rate is already high this keeps stroke volume down.

Standing up on standing blood ‘pools’ in the superficial veins of the legs this is due to gravity so central venous pressure subsequently falls. So by Starlings law, cardiac output falls so arterial pressure falls, so now both arterial and venous pressure changing in the same direction. This cannot be corrected by normal mechanisms. So baroreceptors detect fall in arterial pressure, raise heart rate, but venous pressure sill low. So the TPR increases to defend arterial pressure in the skin and gut. If this reflex doesn’t work this result in postural hypotension.

Haemorrhage – Reduced blood volume lowers venous pressure so cardiac output falls, arterial pressure falls. Baroreceptors detect this fall, so heart rate rises and total peripheral resistance increased.

But rise in heart rate lowers venous pressure further makes problem worse. Heart rate can become very high. Rise in TPR helps arterial pressure but lowers venous, so does not solve original problem. Need to increase venous pressure this is done by constriction of blood vessels conserve blood for vital organ. Also fluid also tens to move from extracellular space into the circulation (auto-transfusion). Water, electrolytes and RBCs eventually replaced.

Note – control systems find it difficult to cope if arterial and venous pressure change in the same direction.

Long term increase in blood volume – the kidney controls blood volume, if blood volume increase for days venous pressure increases, so cardiac output increase so arterial pressure rises. This forces more blood through tissues, which autoregulate and increase TPR so arterial pressure rises further and stays up. In long term blood volume control mechanisms control mean high blood pressure.

Session 7

Cellular and Molecular events in the HeartMyocardial cells – force generated by a contractile apparatus of actin and myosin. This generates tension when [Ca2+]I rises. Tension α [Ca2+]I

[Ca2+]I must rise to produce systole and fall to produce diastole. The rise is due to an action potential.

The equilibrium potential – each ion has an EP which is the hypothetical membrane potential which would develop if it were the only ion that could cross the membrane. If the permeability of the membrane to different ions changes then the membrane potential will change.

Action potentials arise by the action of voltage-gated channels. The whole event is triggered in any one cell by a small starting depolarisation, taking the membrane potential beyond the threshold for opening the fast Na+

channels. For all cells except the pacemaker, this small depolarisation comes about by spread of activity from adjacent cells.

The Cardiac action potential

In diastole the cell membrane of myocardial cells is mostly permeable to K+. So the membrane potential is close to the Ep for K about -80mv.

Spread of activity depolarises ventricular cells. This initial depolarisation is to a threshold which opens fast voltage-gated sodium channels. So move towards the sodium Ep. This in turn opens all the fast Na channels, but fast sodium channels close fast as well. To maintain depolarisation voltage-gated calcium channels open. [Ca2+]o much greater than [Ca2+]I. Calcium rushes into the cell which stimulates release of Ca2+ stores and causes the cell to contract. They stay open for 250ms so the cell contracts for a long time – systole.

When they close the membrane repolarises, aided by extra K+ channels opening, and Ca2+ is sequestered within the cell, so [Ca2+]i falls.

Pacemaker Potential

They have no fast Na channels. The upstroke of their action potential is due to Ca channels opening and is slow.Ca channels also close quickly. Once an action potential has ended the membrane potential is not stable it depolarises slowly (K channels open).

Eventually the pacemaker potential reaches the threshold to open the voltage fated calcium channels so a new action potential begins spontaneously and spreads over the whole heart.

Control of heart rate

The interval between beats depends on how fast the pacemaker potential depolarises. It is speeded up by sympathetic action and slowed by parasympathetic action via the vagus nerve.

Drugs acting on the CVSDrugs are used to treat, arrhythmias, heart failure, blood clotting disorders, angina and hypertension.

They can alter the rate and rhythm of the heart; the force of myocardial contraction; peripheral resistance; blood volume; blood flow to coronary arteries.

Arrhythmias – tachycardia, bradycardia,

Atrial flutter – atria contracting is disorganised

Atrial fibrillation – electrical activity strange resulting no contraction of the atria

Ventricular fibrillation –no co-ordinated contraction of the ventricles.

Causes:

Ectopic pacemaker activity – due to damaged area of myocardium become depolarised and spontaneously active. Also due to latent pacemaker region activated due to ischaemia.

Re-entry loops result in conduction delay.

Drugs to treat arrhythmia

There are 4 basic classes of anti-arrhythmias

Drugs that block voltage-sensitive Na channels (e.g. lidocaine a local anaesthetic) Antagonists of β-adrenoreceptors (beta blockers)

o Block sympathetic action, therefore decrease slope of pacemaker potential in SAN.o Used following myocardial infarction as these increase sympathetic activity. Also

they reduce O2 demand so is obviously beneficial. o Also slow conduction so can prevent supraventricular tachycardias.

Drugs that block K channelso Prolong the action potential, as lengthen the absolute refractory period so prevents

another AP occurring too soon. o Not generally used because they can cause torsades de pointes, another arrhythmiao Used to treat tachycardia associated with Wolff-Parkinson-White syndrome

Drugs that block Ca channels (e.g. verapamil)o Decreases... slope of pacemaker potential at SAN. Decreases... AVN conductiono Decreases force of contraction.o Also causes coronary and peripheral vasodilation.

Heart FailureIt is chronic failure of the heart to provide sufficient output to meet the body’s requirements.

Features: reduced force of contraction, reduced cardiac output, reduced tissue perfusion and oedema.

Drugs

Cardiac glycosides – Ca2+ is extruded via the Na+-Ca2+ exchanger. It is driven by moving down conc. Gradient. Cardiac glycosides block these, so cause a rise in [Na+]i. This rise causes decreased activity of the Na+-Ca2+ exchanger. So [Ca2+]I increases along with the force of contraction.

Also blocks Na+/K+ ATPase, so increase in [Na+]I so inhibition of the Na+-Ca2+ exchanger. So increase

of [Ca2+]I means a positive inotropic effect and increased force of contraction.

Lastly increase vagal activity – so slows AVN conduction and slows heart rate.

ACE-inhibitors - They are drugs which inhibit the action of angiotensin converting enzyme.

They prevent the conversion of angiotensin 1 to angiotensin 2. Angiotensin 2 acts on the kidneys to increase Na+ reabsorption and is a vasoconstrictor.

Its effects: Decrease vasomotor tone (↓ BP), reduced after load of the heart, ↓ fluid retention, reduce preload of the heart, reduce work load of the heart.

Anti-thrombotic DrugsCertain heart conditions carry an increased risk of thrombus formation such as atrial fibrillation acute MI, mechanical prosthetic heart valves.

Anticoagulants Heparin (IV) inhibits thrombin

Warfarin (orally) antagonises the action of vitamin K, used long term. Antiplatelet drugs – aspirin

AnginaIt is myocardial ischaemia, it occurs when O2 supply to the heart does not meet its need. This causes chest pain, usually pain with exertion. It is due to narrowing of the coronary arteries by atheromatous disease.

Treatment – Reduce heart work load - beta blockers, Ca2+ channel antagonists, organic nitrates

And improve the blood supply to the heart – organic nitrates and Ca2+ channel antagonists

NO is a powerful vasodilator.

HypertensionAssociated with increases in blood volume – Na+ and water retention by the kidneys

Treatment – diuretics, ACE-inhibitors, β-blockers, Ca2+ channel antagonists, and α-adrenoreceptor antagonists.

Session 8 – The ElectrocardiogramWith each beat of the heart a large number of muscle cells undergo electrical changes in a precisely defined sequence. The co-ordinated activity of such a large mass of muscle generates a relatively large electrical signal which may be recorded by electrodes attached to the body surface. This is known as the Electrocardiogram.

The electrodes outside of cells only record changes in the membrane potential. Therefore skin electrodes pick up two signals which each systole. One on depolarisation and one on repolarisation.

Spread of excitation over the myocardium also generates a changing signal which electrodes detect. Therefore the ECG is explained by a combination of the effects of depolarisation and repolarisation and their spread over the heart.

Conduction

Is shown to the right it is important to remember the ventricles depolarise inside (endocardial) surface to the outside (epicardial) surface.

Repolarisation in green is in the opposite direction happens 280ms after the depolarisation.

Electrode ‘Views’

What you see depends on where you are looking from Depolarisation moving towards an electrode = upward going signal Depolarisation moving away from an electrode = downward going signal Repolarisation moving towards an electrode = downward going signal Repolarisation moving away from an electrode = upward going signal. The amplitude of the signal depends on:

o How much the muscle is depolarisingo How directly towards the electrode the excitation is moving.

Waves

P wave – atrial depolarisation Q wave – septal depolarisation spreading to ventricle R wave – main ventricular depolarisation S wave – end ventricular depolarisation T wave – ventricular repolarisation.

Atrial repolarisation occurs during ventricular depolarisation i.e. QRS complex so it doesn’t show up.

Lead configurations

By placing electrode in different positions we can ‘look at’ the heart from different angle. This allows detection and localisation of abnormal patterns of electrical activity.

Amplifiers

The amplifiers used to record the ECG have two inputs , not one, so at least two electrodes have to be attached to the body surface. The differential amplifiers used to record the ECGs take the signal coming in on their negative input, invert it then add it to the signal coming in on the positive input before multiplying the sum by a factor known as the gain and then outputting it. By knowing the views of the positive and negative you can therefore combine it to make a single electrode view.

Interpreting the ECGRate - all ECG machines run at a standard rate. Each large square = 0.2s so 300/min

HR = 300/number of squares of the R-R interval. Normal rate approx. 60bpm

Rhythm – regular or irregular, presence of P wave

P wave – absent p wave in atrial fibrillation.

P-R interval – time taken for impulse to reach ventricles 3-5 small squares. Prolonged in first degree heart block and erratic in second degree heart block.

QRS complex – orientation – dependent on the electrical axis of the heart

Width – dependent on the time it takes to depolarise the ventricles – normally 0.12s

Prolonged QRS due to bundle branch block or due to ectopic site and slow pathway.

Axis – Find the lead with the smallest and most equiphasic deflection. The net deflection is zero indicating that the electrical axis must run at right angles to that view usually parallel to lead 2.

If the axis is normal then the depolarising wave is spreading towards leads I, II & III and therefore the deflections in these leads are predominantly upward. If there is right axis deviation the deflection in lead I will become predominantly downward. If there is left axis deviation the deflections in leads II & III will become predominantly downward.

Bundle branch block - lengthens and changes shape of QRS complex, many variations.

ECG: left vs. right bundle block "WiLLiaM MaRRoW":W pattern in V1-V2 and M pattern in V3-V6 is Left bundle block.M pattern in V1-V2 and W in V3-V6 is Right bundle block

MI features – S-T elevation, pathological Q waves and inverted T waves.

Pathological Q waves more than 0.04s wide >2mm deep, remain after other changes resolve.

Sinus Rhythm - When each P wave is followed by a QRS complex

Small Square – 40ms

Heart FailureIt is a state in which the heart fails to maintain an adequate circulation for the needs of the body despite an adequate filling pressure.

It is a pathophysiological state in which an abnormality of cardiac function is responsible for the failure of the heart to pump blood at a rate commensurate with requirements of the metabolising tissues.

It is a clinical syndrome caused by an abnormality of the heart and recognised by a characteristic pattern of haemodynamic, renal, neural and hormonal responses.

Causes: primary cause IHD, hypertension, dilated cardiomyopathy, valvular heart disease, restrictive cardiomyopathy, hypertrophic cardiomyopathy, pericardial disease, high-output heart failure & arrhythmias.

Class 1 – class 4 – No symptomatic limitation of physical activity Inability to carry out physical activity without symptoms, may have symptoms at rest, discomfort increases with any degree of physical activity.

Morbidity – 0.2% of population are hospitalised annually for heart failure

Physiology of the heart

Cardiac output ≈ 5 litres/min Stroke volume ≈75ml/beat LV end systolic volume ≈ 75ml LV end diastolic volume ≈ 150ml Ejection fraction 50% or greater Weight ≈ 330g

Systolic dysfunction

Increased LV capacity Reduced LV cardiac output Thinning of the myocardial wall

o Fibrosis and necrosis of myocardiumo Activity of matrix proteases

Mitral valve incompetence Neuro-hormonal activation Cardiac Arrhythmias

Structural heart changes

Loss of muscle Uncoordinated or abnormal myocardial contraction i.e. ECG changes Changes to the extracellular matrix - increase in collagen (3>1) from 5% to 2% and slippage

of myocardial fibre orientation Myocytolysis and vacuolation of cells Myocyte hypertrophy SR dysfunction Changes to Ca2+ availability and/or receptor regulation

Sympathetic nervous system

Baroreceptor-mediated response causes early compensatory mechanism to improve cardiac output, such as increase cardiac contractility, arterial and venous vasoconstriction and tachycardia. However long-term deleterious effects occur. These are β-adrenergic receptors are down-regulated/uncoupled. Noradrenaline – induces cardiac hypertrophy/myocyte apoptosis and necrosis via α-receptors and induces up-regulation of the RAAS. Also long term reduction in heart rate variability.

Renin-Angiotensin-Aldosterone System

RAAS commonly activated in HF and causes reduced renal blood flow and SNS induction of renin from macula densa.

Elevated Angiotensin II:

Potent vasoconstrictor Promotes LVH and myocyte dysfunction Promotes aldosterone release Promotes Na+/H2O retention Stimulates thirst by central action.

Anti-diuretic hormone

Hypo-natraemia results from H2O in excess of Na+ retention and can be due to; increased thirst and action of ADH on V2 receptors in the collecting duct

Normally hypo-natraemia/hypo-osmolality inhibits ADH release – but ADH is increased in HF:

Increased H2O retention and tachycardia and reduced systemic resistance resulting in increased CO.

Endothelin – Secreted by vascular endothelial cells, it is a potent system and renal vasoconstrictor acting via autocrine activity thus activating RAAS. Can increase with heart failure.

Bradykinin – promotes natruiresis and vasodilatation and stimulates production of PGs.

Increase in peripheral arterial resistance by SNS, RAAS, reduced nitrates and increased endothelin.

THIS LEADS to

Skeletal muscles changes – reduced blood blow flow, reduction in mass, contribute to fatigue and exercise intolerance

Renal effects - Glomerular filtration rate maintained in early HF by haemodynamic changes at the glomerulus. Increased Na+/H2O retention due to neuro-hormonal activation. However eventually renal blood flow falls leading to reduced glomerular filtration rate and a subsequent rise in serum urea and creatinine. This can be exacerbated by treatment inhibiting the actions of angiotensin 2.

Diastolic Dysfunction

Factors: frequently elderly and female, often history of hypertension/diabetes/obesity

Normal LV function but concentric LVH.

Reduced LV compliance, impaired myocardial relaxation, impaired diastolic LV filing (with increased LA and PA pressures). Unable to compensate by increasing LV EDP. Low cardiac output results, this triggers neuro-hormonal activation as per systolic heart failure.

In clinical practice, heart failure is often divided into:

Right sided heart failure, left sided heart failure, biventricular cardiac failure, systolic heart failure, diastolic heart failure. It is rare for any part of the heart to fail in isolation.

Left heart failure: fatigue, exertional dyspnoea, orthopnoea, paroxysmal nocturnal dyspnoea.

Mild: tachycardia, cardiomegaly, 3rd or 4th heart sound, functional murmur of mitral regurgitation, bascal pulmonary crackles and peripheral oedema.

Right heart failure: chronic lung disease, pulmonary embolism/pulmonary hypertension, pulmonary/tricuspid valvular disease, left to right shunts, isolated right ventricular cardiomyopathy. The most frequent cause is secondary to left heart failure. Related to distension and fluid accumulation in areas drained by the systemic veins: Jugular vein pressure increased, tender, smooth hepatic enlargement, dependent pitting oedema, ascites (peritoneal cavity) and pleural effusion.

Management of Heart failure

Lifestyle modification- reduce salt, decrease alcohol, increase aerobic exercise, decrease BP.

Pharmacological – diuretics, ACE, nitrate, β-blockers, spironalactone (diuretic), digoxin, antiarrhythmics

Cardiac surgery – heart transplantation, mechanical assist devices, underlying cause, valve surgery, revascularisation.

Implantable pacemakers – biventricular pacing

Implantable defibrillators.

Special CirculationsDifferent parts of the circulation have different properties.

The pulmonary circulation

The lungs have two circulations:

The bronchial circulation – part of the systemic circulation is there to meet the metabolic requirements of the lungs

Pulmonary circulation – blood supply to alveoli, required for gas exchange. Entire right output of the heart is directed through this. It is not demand led like the systemic but instead it is supply driven.

The pulmonary circulation works with low pressure and low resistance.

Where Pressure (mmHg)Right atrium 0-8Right Ventricle (15-30)/(0-8)Pulmonary artery (15-30)/(4-12)Left atrium 1-10Left ventricle (100-140)/(1-10)Aorta (100-140)/(60-90)

Low Resistance due to short, wide vessels, lots of capillaries and arterioles have relatively little smooth muscle.

There is efficient gas exchange, as loads of capillaries, short diffusion distance 0.3 цm.

For efficient oxygenation we need to match ventilation of alveoli with perfusion of alveoli. So we divert blood from alveoli which are not well ventilated.

Hypoxic pulmonary vasoconstriction ensure optimal ventilation perfusion ratio. This is the most important mechanism regulating pulmonary vascular tone, alveolar hypoxia results in vasoconstriction of pulmonary vessels. This ensures that perfusion match ventilation

Although chronic hypoxic vasoconstriction can cause RV failure, caused by altitude or lung disease. Chronic increase in vascular resistance means chronic pulmonary hypertension, high afterload on right ventricle...

Exercise

Increase cardiac output. Small increase in pulmonary arterial pressure, opens apical capillaries so increased O2 uptake by lungs, as blood flow increases capillary transit time is reduced.

Fluid

The pressure in the pulmonary capillaries is normally less than the colloid osmotic pressure. So tissue fluid is not normally formed in the lungs. There is no overall control of the pulmonary resistance. But the pulmonary arterioles can control the distribution of the cardiac output over the lung.

Though increased capillary pressure causes more fluid to filter out oedema. Can be due to increased venous pressure (due to mitral valve stenosis and LV failure).

Pulmonary oedema impairs gas exchange, use diuretics to relived symptoms and treat underlying cause.

Gravity also influences the distribution of blood flow through the lungs, as when standing, the transmural pressure within blood vessels at the base of the lungs sis elevated by gravity. This may lead to some filtration of tissue fluid, but will also distend the vessels and increase flow to those areas. An example of ventilation/perfusion mismatch is causes by gravity, because gravity increases blood flow to the base, where more is being delivered to the top. So some blood actually passes though without being oxygenated - called the ‘physiological shunt’

Cerebral Circulation

The brain gets 15% of cardiac output but only 2% of body mass, but at rest grey matter accounts for 20% of the bodies oxygen consumption.

It meets this by having a high capillary density, short diffusion distance, high basal flow rate X10 average for whole body and high O2 extraction rate – 35% above average.

Neurones are very sensitive to hypoxia, loss of consciousness after a few seconds of cerebral ischaemia. Approximately 4 mins for irreversible brain damage.

Structurally – anastomoses between basilar and internal carotid arteries

Functionally – brainstem regulates other circulations, myogenic Autoregulation maintains perfusion during hypotension. Metabolic factors control blood flow.

Areas with increased neuronal activity have increased blood flow

Adenosine is a powerful vasodilator of cerebral arterioles

Cushing’s Reflex

Rigid cranium protects the brain, but does not allow for volume expansion. Increases in intracranial pressure impairs cerebral blood flow – could be due to cerebral tumour or haemorrhage. Impaired blood flow to vasomotor control regions of the brainstem increase sympathetic vasomotor activity which in turn increases arterial BP and helps maintain cerebral blood flow.

Blood Brain barrier lipid soluble molecules such as the O2 and CO2 can diffuse freely, lipid insoluble solutes can’t.

Coronary Circulation

Right and left coronary arteries arise from aortic sinuses, must deliver at a high rate.

Blood flow into the left coronary artery is mainly during diastole.

Capillary density of cardiac muscle is much higher than skeletal. Also continuous production of NO by coronary endothelium which maintains a high basal flow.

Coronary arteries

Few arterio-arterial anastomoses prone to atheromas. This leads to angina on exercise. Blood flow mostly during diastole so diastole is reduced as heart rate increases. Stress and cold can also cause sympathetic coronary vasoconstriction and angina. Sudden obstruction by thrombus causes myocardial infarction.

Skeletal muscle circulation

It must increase O2 and nutrient delivery and removal of metabolites during exercise. It has an important role in helping to regulate arterial blood pressure – 40% of adult body mass. Resistance vessels have rich innervation by sympathetic vasoconstrictor fibres – Baroreceptor reflex maintains blood pressure.

Capillary density depends on muscle type. Postual muscles have higher capillary density.

They all have very high vascular tone, which permits lots of dilatation flow can increase 20 times in active muscle. At rest only ½ of capillaries are perfused at any one time – so allows for recruitment.

Vasodilators K+, osmolarity, inorganic phosphates, adenosine and H+ (all increase)

Adrenaline as well. By acting on β2 receptors and vasoconstrictor response via NA on α1 receptors.

Cutaneous Circulation

Its main function is to maintain a constant body temperature. Skin is the main heat dissipating surface – this is regulated by cutaneous blood flow.

Acral (apical) skin has specialised structures called artereovenous anastomoses (AVAs).

Apical skin has a high surface area to volume ration. They are under neurl control. Not regulated by local metabolites. Decrease core temperature increases sympathetic tone in AVAs decreses blood flow to apical skin. Increased core temperature opens AVAs.

Cardiac DiseaseCauses of chest pain: angina, MI, syndrome X, pericarditis aortic dissection, aortic aneurysm, PE, infection, heart burn, peptic ulcer, costochondritis and cervical thoracic disc degeneration.

Ischaemic heart diseaseCoronary heart disease – caused entirely by atherosclerosis. Starts with fatty streak, lipid laden foam cells – macrophages and partly smooth muscle. Progression to fibro-lipid plaque depends on age and risk factors.

Risk factors for CAD

Increasing age, male sex, family history, hypertension, high total cholesterol, low HDL-cholesterol, cigarette smoking, diabetes, LV hypertrophy, obesity, lack of physical activity, alcohol.

Stable angina

Symptom, not a diagnosis, commonest cause of coronary artherosclerosis. One major artery >70% reduction in luminal diameter, pain on exercise. ECG may be normal but sometimes ST depression is shown. Exercise testing and angiography.

Treatment – angioplasty for symptomatic relief, coronary bypass (if 3 vessels blocked), control of BP, stop smoking, lose weight, control diabetes, control lipids and exercise.

Drugs: aspirin, nitrates, beta blockers, Ca2+ channel antagonists (arterial vasodilatation), Nicorandil (KATP channel activator – coronary vasodilator activity)

Unstable Angina and Non S-T elevation MI (NSTEMI)

Recent onset angina, angina occurring with increasing frequency occurring with less exertion and or at rest. Not rapidly relieved by GTN, related to plaque rupture and thrombus formation. >90% occlusion.

Unstable angina: limited duration and extent of obstruction no necrosis

NSTEMI- makers of cardiac necrosis will be present.

Treatment: admit to CCU, oxygenate, pain relief, aspirin, clopidogrel (reduction in platelet adhesion), Heparin, glycoprotein receptor antagonists (reduce binding of fibrinogen), then treat like stable angina.

STEMI

Myocardial necrosis secondary to acute interruption of coronary blood supply. Rupture of plaque, intra-coronary thrombus and hence coronary occlusion. Necrosis of full thickness of myocardial wall. Chest pain is more severe and strong sympathetic reaction.

Presentations similar to NSTEMI but complication in 30%:

Arrhythmias, cardiogenic shock, LV failure.

ECG changes. First hours ST elevation, first 24 hours T wave inversion, pathological Q after 24 hours. Long term Q wave stays (90% of cases) and T inversion (rarer) but ST elevation remaining is extremely rare.

Maybe ST depression in leads not next to infarct.

Enzymes: after MI creatine kinase, SGOT, and lactase dehydrogenase are released peaking at various times after, in that order. Also troponins present from the beginning and last a long time.

Treatment: thrombolysis and angioplasty

To maintain arterial patency – anti-platelet therapy: aspirin, clopidogrel. Anticoagulants and beta blockers.

Cardiac ArrestHeart has stopped or has ceased to pump effectively. signs unresponsiveness associated with lack of pulse.

Asystole – loss of electrical and mechanical activity.

Ventricular fibrillation – uncoordinated electrical activity

most common form of cardiac arrest May occur following MI or can result from electrolyte imbalance (e.g. hyperkalaemia)

Treatment: BLS – chest compression and external ventilation ALS – defibrillation, electrical current delivered to heart which depolarises all the cells and puts them into refractory period that allows coordinated electrical activity to restart. Adrenaline enhances myocardial function and increases TPR.

Shock – Session 12Shock is the acute condition of inadequate blood flow throughout the body. A catastrophic fall in arterial blood pressure leads to circulatory shock.

Blood pressure = cardiac output X total peripheral resistance.

Either fall in CO or a fall in TPR beyond the capacity of the heart to cope.

Cardiogenic shock

Pump failure the ventricle cannot empty properly. Occurs following MI or due to serious arrhythmias or worsening of heart failure. Central venous pressure (CVP) may be normal or raised. Heart fills, but fails to pump effectively resulting in ↓BP. Tissues poorly perfused such as coronary arteries and kidneys.

Mechanical shock

Cardiac tamponade: restricts filling of the heart and limits end diastolic volume, affects both sides of the heart. High central venous pressure but low arterial BP.

Large Pulmonary embolism: Right ventricle cannot empty, pulmonary artery pressure is high, reduced return of blood to left heart, limits filling of left heart. Left arterial pressure is low, arterial blood pressure is low. SHOCK. symptoms chest pain and dyspnoea.

Hypovolaemic shock

Reduced blood volume, probably due to haemorrhage. >20% reduction in blood.

Haemorrhage venous pressure falls, CO falls, arterial pressure falls.

Compensatory response increased sympathetic, tachycardia, positive inotropy, peripheral vasoconstriction and venoconstriction. Internal transfusion increased peripheral resistance reduces capillary hydrostatic pressure so net movement of fluid into the capillaries.

Symptoms: tachycardia, weak pulse, pale skin and cold extremeties.

Decompensation peripheral vasoconstriction impairs tissue perfusion. Tissue damage due to hypoxia, release of chemical mediations – vasodilators TPR falls BP falls vital organs not perfused resulting in multi organ failure.

Distributive shock

Normovolaemic but profound peripheral vasodilation - ↓ TPR. blood volume constant, but volume of the circulation has increases.

Split into Septic/toxic shock and anaphylactic shock

Toxic: Septicaemia caused by endotoxins released by circulating bacteria cause massive vasodilation ↓TPR ↓arterial pressure ↓ perfusion to vital organs. Also capillaries become leaky which reduces blood volume. Baroreceptors notice ↓ BP so increase sympathetic output. Vasoconstriction overridden by vasodilators but CO increased.

So patient has tachycardia, strong pulse and warm, red extremities.

Anaphylactic: Severe allergic reaction histamine released from mast cells (and others) vasodilator effect ↓ TPR arterial pressure ↓ sympathetic kicks in but CO ↑ can’t overcome vasodilation impaired perfusion of organs. Mediators also causes bronchoconstriction.

Symptoms difficulty breathing, collapsed, tachycardia, strong pulse and red, warm extremities. Needs adrenaline vasoconstriction via alpha 1 adrenoceptors.

Hypertension

Hypertension is a sustained increase in arterial blood pressure. Regulation at 3 sites:

Kidneys blood volume Heart cardiac output Vasculature TPR

LDH

creatinekinase

aspartatetransferase

long term causing LV hypertrophy risk of heart failure

Risk of arterial disease of coronary arteries, cerebrovascular system, renal vasculature, retina and aorta.

Hypertension is defined as greater than 140 systolic or over 90 diastolic.

Treatment weight loss, exercise and less salt

drugs: diuretics, vasodilators (calcium channel blockers), ACE inhibitors and beta blockers.