Electrical Activity of the Heart The Cardiac Cycle

Regulation of Cardiac Output

Anti-Arrhythmic Drugs Heart Failure

The heart is formed out of two

types of muscle cells
o Cardiac Myocytes o Cells of the cardiac

pacemaker-conduction system

The cells of the pacemakerconduction system generate an electrical signal

Propagated signal elicits

myocytes contraction

Cardiac myocytes arranged in an end-end fashion separated by intercalated discs At rest, there is high PK+ & low PNa+, PCa2 +

Resting potential at rest is

stable Depolarisation threshold of -65mVs Depolarisation caused by influx of Na + and Ca2 +

Unique plateau phase -

inward current of Ca2 +

Results in long refractory periods

Repolarisation occurs via efflux of K+

Initial resting potential of -70 mVs

Electrically unstable automatically generates repetitive rhythmic action potentials

Due to unique recycling changes in the PK + , PNa2+ , PCa2 +

Threshold potential is -50 mVs Depolarisation is facilitated by influx of Na2+ and Ca2 +

The SAN has intrinsic rate of 100 bpm; AVN 40 bpm

Repolarisation is facilitated by

K+

efflux

AVN adds 100 msec delay

Parasympathetic Vagus (CN X)

o Innervates SAN & AVN predominantly

o Decrease HR by decreasing SAN firing frequency and increasing AVN

delay

Sympathetic
o SAN, AVN and ventricular muscle o Increase HR by increasing SAN firing frequency and decreasing AVN

delay
o Increase ventricular contractility

Normal heart beat 70 bpm Cycle duration 850 msecs; two thirds in diastole Relative pressure gradient between chambers and their outlets

determine position of the valves

1st heart sound = AV valve closure 2nd heart sound = Aortic & pulmonary valve closure

EDV = volume in left ventricle at the opening of the aortic valve

ESV = volume at closure of aortic valve

CO is total volume of blood ejected from the left ventricle into the
systemic circulation per unit of time

CO = HR x SV ; CO = ABP/TPR SV is dependent on 2 opposing factors:

o Energy of myocyte contraction o TPR(After load)

Energy of myocyte contraction is in turn dependent on two processes:

o Myocyte contractility o EDV (Pre-load)

Innate strength with which a myocyte contracts from a given initial stretch

Increased by nervous, hormonal and chemical influences

1. 2.

Is dependent on Ca2+ induced Ca2+ release from the SR

Ca2+ binds to Troponin on the Tropomyosin Frees the Myosin binding sites on Actin filament

3.
4.

Leads to the formation of cross links

ATP hydrolysis facilitates breakage of cross links which pulls the filament towards the centre of the sarcomere

Through his experiments, Starling found that if other factors such as TPR and ABP are kept constant, an increased EDV leads to an increased SV Increased EDV due to increased venous return leads to:
1. Increased EDP
2. Greater distension and stretch of ventricular myocytes more

filament overlap
3. Ventricles develop greater contractile energy

4. Larger SV

The force of ventricular contraction depends on the length of the ventricular muscle fibres during diastole (EDV)

HR - >180 bpm Atrial Contraction at high rates, EDV is more atrial dependent TPR reduce stroke volume and therefore increase ESV

CVP largest influence on EDV of the right heart

o Increased blood volume o Increased activity of skeletal muscle pump

o Increased activity of the respiratory pump

o Increased venous tone o Posture

Clinical syndrome arising from an inability of the heart to produce

a cardiac output that is sufficient for the metabolic demands of

the body

Caused either by intrinsic diseases of the myocardium (i.e. cardiomyopathies) or by chronic overloading of the myocardium (i.e. valvular disease/hypertension)

Symptoms include dyspnoea, PND, orthopnea and peripheral oedema

Causes a rightward shift in Starling curve SV is reduced at normal

filling pressures

HF leads to the activation of compensatory neuro-hormonal

mechanisms

Whilst this initially compensates for the reduced CO, chronic activation leads to increases in the pre & after load, thus increasing cardiac work

Aims of treatment are two fold:

o Block the pathways that cause further deterioration o Improve symptoms

Drugs used:
o Diuretics o ACE Inhibitors o AT Receptor Antagonists o Aldosterone Receptor Antagonists o Cardiac glycosides o Vasodilators o - blockers

Elastic Arteries Arterioles

Capillaries
Venous Vessels Pulmonary Circulation Coronary Circulation

ABP = CO x TPR; MABP = DP + 1/3(PP)

Elastic arteries are the

primary site where ABP is determined

Coverts the intermittent flow into continuous flow

Can distend under pressure to accommodate blood

flow during systole and

maintain blood pressure during diastole by recoiling

This is due to the distinct

biomechanical properties conferred by

the tunica media

During systole, opening of aortic valve results in the

ejection of the SV into the

aorta

Approximately 20% of the ejected blood flows straight through the vessels

80% distends the aorta and this stretching is stored as

During diastole, elastin

recoil returns this energy to the blood to maintain flow

potential energy

This creates a travelling pressure wave

The composition of the elastic arteries is prone to change with age There is loss of elasticity of the tunica media leading to a decrease in compliance

This increased rigidity leads to an increase in the SBP The decreased recoil results in a decrease in DBP Leads to age dependent increase in PP

Blood is a homogenous fluid Flow is in a laminar pattern Each successive laminae from the edge to the centre is of a higher

velocity

Maximum velocity is at the centre of the vessel which is occupied by RBCs

Laminar blood flow is silent

Blood may also be turbulent

Here the currents swirl in random moving patterns

Dissipates pressure energy as heat and sound

Occurs during high blood velocities, pregnancy, hyperthyroidism and at sites of atheroma formation

Turbulent flow leads to bruit

SBP

DBP

Increased SV Increased Contractility High CO states

Increased TPR Increases in HR

Main site of resistance in the vascular system and therefore the main component of the TPR

Through constriction and dilatation, arterioles can increase or

decrease ABP

As such they are the main regulators of ABP This is due to the higher density of smooth muscle and sympathetic receptors allowing arterioles to exhibit wider control of changes in the

diameter in reaction to local influences

Endothelium derived substances

o NO, PG2

Myogenic tone
o An increase in BP causes vasoconstriction allowing flow to remain the

same

Metabolic vasodilators
o Dilatation caused by products of metabolism

Nerve fibres
o Sympathetic supply to arterioles evoke constriction. Parasympathetic

supply to arterioles of the brain, heart and genitalia causes dilatation

Hormones
o Circulating noradrenaline causes constriction whilst adrenaline causes

dilatation in the skeletal muscle. ADH and AII cause constriction

Relative constancy of flow despite changes in ABP

over a certain range

Thought to occur through myogenic tone

Independent of neurohormonal influences

The delivery of metabolic substrate to tissues occurs across the capillary wall

It is also the site of fluid exchange between the plasma and the interstitial compartments

Capillaries do not have any smooth muscle they are of a fixed

resistance

Blood velocity is lowest in the capillaries which in conjunction with the increased TSA make the region ideal for exchange

Exchange can occur through two mechanisms:

o Diffusion o Filtration

The rate of diffusion is dependent on:

1. The permeability of the capillary

2. The concentration gradients across the capillary walls

3. The surface area available for diffusion

Mathematically= P x (C1-C2) x A

Passive movement of fluids across the capillary wall

The net rate/direction of fluid across any given segment of the

capillary wall depends on the net filtration pressure

Net filtration pressure = hydrostatic pressure gradient the oncotic

pressure gradient
o CHP = 35 mmHg; decreases to 15 mmHg at venous end o THP = 0 mmHg

o COP = 25 mmHg
o TOP = 2-3 mmHg

Arteriolar constriction
o Increase arteriolar resistance and reduce downstream flow and

pressure
o This will cause momentary cessation of blood flow thus reducing

capillary surface area available for diffusion and decrease the CHP
o Lead to decreased filtration

Arteriolar dilatation
o Decrease resistance and increase downstream flow and pressure o This will increase capillary recruitment and CHP o Lead to increased filtration o This can lead to oedema if the lymphatic system cant cope

Increased CHP Fluid out > Fluid in

Decreased CHP Fluid out < Fluid in

Changes in capillary or tissue oncotic pressure can also affect the net filtration process An increase in COP will lead to greater reabsorption of fluid This will increase blood volume and can occur due to water loss, diarrhoea, vomiting and profuse sweating Conversely a decrease in COP will lead to greater filtration This will lead to oedema and can be due to decreased synthesis of plasma proteins or increased loss of plasma proteins Whilst the TOP is relatively small, it may increase when the vascular permeability increases during inflammation This will decrease the oncotic pressure gradient and favour filtration

Increased COP Fluid out < Fluid in

Decreased COP Fluid out > Fluid in

(Increased TOP)

Compared to arteries and arterioles, veins have:

o Greater compliance o Larger proportion of the

blood volume
o Larger diameter o Larger cross sectional area o Lower resistance o More branched o Have valves

Compliance is a feature of collagen found in the walls of the vein

In a low volume supine state, the collagen is pleated

As volume increases, the collagen unfolds allowing for a more rounded shape

Veins also have smooth muscle in the

tunica media which can contract upon sympathetic stimulation

This limits the distension of a vein and therefore makes them less compliant

1.

Veins are one of the determinants of filtration of fluid across

capillaries
2.

Veins act as a major reservoir of blood which can be mobilised depending on the bodys need

3.

Veins are an important determinant of the EDV of the right heart

The pressure in veins depends on how much volume they contain

and the state of their smooth muscle

Passive influences:
o Blood volume o Posture o Skeletal muscle pump o Respiratory pump

Active influences:
o Sympathetic NA nerve activity

Low pressure Loss of pressure from arteries to capillaries is more gradual

MPABP is approximately 12-14 mmHg

Low resistance
Larger diameter Shorter in length

High compliance

Passive influences:
o Blood volume o Posture

Active influences:
o Sympathetic nerve activity o Hypoxia o Chemical mediators such as histamine and bradykinin

Provides oxygen at a high rate to keep pace with cardiac demand

Two main arteries : RCA & LCA Receives 3-4% of the total CO which equates to 80-90 mls of oxygen per min per 100 g of muscle

Large percentage of oxygen extraction by the myocardium 70% -

80%

The branches of the coronary artery (particularly LCA) within the myocardium are exerted to compression during each ventricular systole

During systole, LV pressure rises to 120 mmHg, pushing blood through

the aorta and coronary vessels at the same pressure

However as coronary vessels enter the depths of the myocardium, they get smaller and increase in resistance

The pressure here reduces to 80 mmHg As such during systole, there is occlusion of the myocardial coronary vessels due to mechanical compression from the LV

During diastole, ventricular relaxation results in a decrease in LV pressure to about 8 mmHg

The recoil of the elastic arteries maintains an initial coronary pressure of 80 mmHg

Again due to the increased resistance, the coronary vessels of the

inner myocardium have a minimal pressure of 40 mmHg

However since this is greater than the LV pressure, there is no occlusion of the vessels

Note: The right ventricular pressures are always lower than the systolic and diastolic blood pressures and as such there is no occlusion of blood flow. However overall average flow is the RCA is lower.

CW = CO x ABP Increased CW may be associated with:

o Increased HR o Increased Contractility o Increased Afterload

An increase in CW cant be accommodated by an increase in oxygen extraction -maximum extraction is approximately 85%

Furthermore the myocardium has little capacity for anaerobic metabolism

Increases in cardiac work must therefore be matched by an increase in blood flow to the heart by vasodilatation

Increased myocardial metabolism Systemic Hypoxia Decreased coronary flow

Myocardial hypoxia

Activates 5 nucleotidase

5 nucleotidase catalyses the formation of adenosine from AMP. Adenosine accumulates in the interstitial fluid and induces coronary vasodilatation

This mechanism is occurring continuously even at rest

However if cardiac work increases and an individual doesnt have a large capacity for further vasodilatation, angina develops

Therefore it can be seen that the local factors of mechanical compression and chemical factors involving adenosine are the most important influences on coronary flow

The coronary vessels also receive sympathetic and parasympathetic nerve supply

Increased sympathetic NA activity causes vasoconstriction

Increased Parasympathetic cholinergic activity causes

vasodilatation

However in both these effects tend to be overcome by the effects on CW and subsequent adenosine release

Usually caused by coronary artery disease secondary to atherosclerosis

Treatment:
o Vasodilators o blockers o Diuretics o PCTA or CABG

Variant angina is pain associated with a constant level of cardiac work. This occurs because of coronary artery spasm possibly due to selected activation of sympathetic fibres leading to vasoconstriction

Baroreceptor reflex
Atrial Volume reflex Orthostasis Cardio-Respiratory Interactions Exercise reflex The Alert-Defence Response

The baroreceptor reflex is the predominant homeostatic regulator of

ABP on a beat to beat basis

The baroreceptors are stretch receptors that are located in two specific locations:
o The carotid sinus o The aortic arch

They respond to changes in the ABP via the stretch it evokes on the arterial wall

Stimulation brings about reflex mechanisms which return ABP to the normal value

Baroreceptors are continually active and

monitor ABP via the stretch it

causes

Afferent nerve activity reflects the changes in the pressure exerted within the artery

Receptors are not only

sensitive to the amount of

stretch, but also the rate of change

Increased ABP

Increased Baroreceptor Activity

CNS

Increased parasympathetic outflow

Decreased sympathetic outflow 1. 2. 3. 4. Arteriolar vasodilatation Venous vasodilatation Decreased HR Decreased contractility

1. Decrease HR Overall: Decrease CO Decrease TPR Decrease ABP

Decreased ABP Decreased Baroreceptor Activity CNS

Decreased parasympathetic outflow

Increased sympathetic outflow 1. 2. 3. 4. Arteriolar vasoconstriction Venous vasoconstriction Increased HR Increased contractility

1. Increase HR Overall: Increase CO Increase TPR

Increase ABP

Afferent fibres via CN IX and X enter the NTS these are excitatory neurones

NTS sends inhibitory neurones to the pre-motor sympathetic neurones in the brain

Also sends neurones to the pre-optic hypothalamus which in turn also send inhibitory signals to the pre-motor sympathetic neurones

The NTS also sends excitatory neurones to the NA This increases vagal tone to the heart A final branch is sent to the supra-optic and paraventricular nuclei which inhibits ADH release from the posterior pituitary

GIT and skeletal muscle vasoconstriction The skin if in thermal balance will undergo vasoconstriction If there is a large change in ABP, there will be renal vasoconstriction

This will lead to further constriction via activation of the RAAS

The cerebral and coronary circulation is not affected as they lack a large sympathetic supply

Volume receptors are located in the right atrium

They are stretch receptors that respond to increased venous return

Send afferents via CN X to the NTS Increased stimulation brings about reflex changes which return atrial volume to normal

Reflex has two components:

o Transient increase in sympathetic supply to the heart o Large decrease in sympathetic activity to the kidneys and

the pituitary gland

Bainbridge reflex

Main reflex

NTS increases sympathetic

NTS decreases sympathetic

supply to the kidneys leading to vasodilatation

stimulation of the heart

Increases the HR Reduces the time the heart

has to fill and prevents overstretching of the atria

This reduces activation of the

RAAS

Initial protective function Overall: Decrease venous return

Furthermore NTS inhibits pituitary secretion of ADH

This reduces fluid retention

Decrease atrial filling

When supine, ABP is uniformly distributed throughout the body at approximately 95 mmHg

At the level of the heart it is 100 mmHg Similarly venous pressure is uniformly distributed through the body at 5 mmHg

At the level of the heart it is 3 mmHg

95 mmHg 5 mmHg

100 mmHg 3 mmHg

95 mmHg 5 mmHg

Upon standing, there is a redistribution of blood towards the lower extremities 55 mmHg -35 mmHg 100 mmHg 1 mmHg

195 mmHg 105 mmHg

Upon standing, the increased venous pooling will decrease the CVP

causing less stimulation of the atrial volume receptors

This will decrease REDV and RSV Subsequently there will be a decrease in LEDV and LSV This will decrease the CO and the ABP This will cause decreased stimulation of the baroreceptors As a consequence of the reflex, there is tachycardia, vasoconstriction and increased contractility

Ultimately this increases ABP

Respiratory influences on the heart can take the form of mechanical

and neural influences

The mechanical influence involves the respiratory pump The neural interaction causes an increase in HR during inspiration This is physiologically normal and known as RSA Inspiration

Increased HR

Decreased HR

Expiration

Mechanism 1 During inspiration, the inspiratory centre in the medulla sends inhibitory

Mechanism 2
This is a reflex mechanism involving pulmonary stretch receptors in the airways

signals to the NA via the

central inspiratory neurones

Inspiration causes widening of the airways, increasing the afferent activity from these receptors to the NTS via CN X

This reduces vagal tone to the heart resulting in tachycardia

This causes the NTS to send inhibitory signals to the NA leading to tachycardia

Mechanism 2 Mechanism 1

Peripheral chemoreceptors are responsible for the homeostatic regulation of primarily Pa02

These receptors are located in the carotid and aortic bodies, in

close proximity to the carotid and aortic baroreceptors

Reflexes from the peripheral chemoreceptors include:

o Primary cardiovascular reflex o Secondary cardiovascular response

Conserves O2 when respiration cant increase

Decreases HR and causes vasoconstriction Afferents to the NTS which in turn stimulates the NA and causes bradycardia

NTS also stimulates the pre-motor sympathetic fibres leading to vasoconstriction

A final pathway from the NTS stimulates the respiratory centre in the brain and stimulates the inspiratory motor neurons but respiration cant increase due to other pathology/environment

When respiration can increase, systemic hypoxia evokes tachycardia in addition to vasoconstriction

Increased respiration leads to modulation of the primary cardiovascular reflex

This occurs via:

o Activation of the pulmonary stretch receptor reflex o Direct inhibition of the NA from the inspiratory centres of the brain

Reflex elicited by stimulation of the trigeminal afferents in the

face/nose

Trigeminal afferents travel to the NTS which sends inhibitory neurones to the inspiratory centre

This result in total inhibition of the central inspiratory drive This leads to expiratory apnoea There is increased NA activity leading to bradycardia In addition the increased sympathetic tone to the vessels leads to vasoconstriction

Two types of exercise:

o Static
o Dynamic

Both forms of exercise evoke some CV changes:

o HR increases o CO increases o Blood flow increases

The cardiovascular response to exercise involves the exercise reflex superimposed upon the local responses to metabolic activity in the muscles and the heart

During static exercise, the heart rate increases in proportional to the amount of exercise done

During dynamic exercise, again the HR increases in proportional to the amount of exercise done

However the increase is usually greater compared to static exercise

During static exercise, blood pressure increases in proportion to the

level of exercise

This is due to the compressive impairment of muscle perfusion which increases the activity of the muscle metaboreceptors

This leads to a strong exercise pressor reflex which causes

vasoconstriction

During dynamic exercise, the increase in CO is nearly totally

balanced by a fall in TPR and therefore mABP changes very little

SBP increases due to the increased HR and CO However DBP does not increase and may even fall

During static exercise, there is an overall increase in blood flow The greatest increase in blood flow occurs during relaxation This is because contracting muscle exerts a mechanical occlusive force on the blood vessels, thus increasing the resistance

During dynamic exercise, here is also a general increase in blood flow

The increase occurs regardless of contraction/ relaxation This is because dynamic exercise involves cycles of contraction/relaxation and there is no great occlusive effect on the vessels

Reflex is elicited by metaboreceptors located in the muscle These are free nerve endings in the interstitial space between muscle fibres

Upon stimulation by metabolites, they send afferents to the

hypothalamic locomotor region

Via efferent pathways, the reflex response involves:

Increase in respiration
Increase in HR Increase in contractility

The exercise reflex also increases sympathetic NA supply to the

skeletal muscles, GIT and kidneys

This mediates vasoconstriction However working muscles overcome this neural influence via local metabolic hyperaemia

Negligible role during mild to moderate exercise They respond predominantly to changes in PaO2 and PaCO2 Central chemoreceptors are responsible for responding to changes

in PaCO2

Peripheral chemoreceptors are responsible for regulating PaO2 However the peripheral chemoreceptors may also respond to

arterial pH during severe exercise which induces acidosis

Emotional stress, noxious stimuli, novel stimuli and very strong

peripheral chemoreceptor stimulation can all elicit an alerting response

There is no one particular receptor responsible for evoking this response

Rather it is evoked by a variety of afferent signals to the integrating area for the defence response

This pattern of response is stereotyped regardless of the original

eliciting stimuli

The magnitude of the response is dependent of the strength of the stimulus

The alerting response is common to mammalian species

The response can show habituation or sensitisation

It can be conditioned Activation of the alert response suppresses the baroreceptor reflex

Located primarily in the hypothalamus However there are multiple connections from the hypothalamus to other important areas:
o To the amygdaloid defence area

o Up past the fornix to the stria terminalis

o Stria terminalis in turn sends connections back to the amygdaloid

defence area

This forms a circuit between the 3 regions which positively reinforces the pathway meaning that the response can often outlast the stimulus

Connection back to amygdaloid defence area

Connection to stria terminalis

Connection to amygdaloid defence area

The prefrontal cortex provides either positive or negative modulation via the main integrating areas

From the defence area, connections leave the brain via the ventral medulla from where synapses to the efferent nerves are formed

In type A personalities, continuous or repeated exposure to stressful stimuli may lead to strong alerting responses

Repeated activation and subsequent suppression of the baroreceptor

reflex may be associated with the development of essential

hypertension

This is supported by the link between essential hypertension, stress levels and type A personalities

Furthermore there is also the acute dangers of an uncontrolled rise in ABP in patients with cerebrovascular disease, coronary artery disease and aortic aneurisms

GIT and skeletal muscle vasoconstriction The skin if in thermal balance will undergo vasoconstriction If there is a large change in ABP, there will be renal vasoconstriction

This will lead to further constriction via activation of the RAAS

The cerebral and coronary circulation is not affected as they lack a large sympathetic supply

Anti Arrhythmic Drugs Cardiovascular Autonomic Pharmacology Vasodilators Ageing and Syncope Hypertension and therapeutic intervention

Any Questions? MXA962@bham.ac.uk