cardio learning topics block 5

LEARNING TOPICS - BLOCK 5

Cardiovascular Sciences

Activation of the heart1.Assessing peripheral vascular disease2.Atrial fibrillation3.Causes of heart failure4.Causes of tiredness5.Chromosomal abnormalities and early development in Down syndrome6.Chronic viral infections7.Clinical and laboratory assessment in heart failure8.Complications of ischaemic heart disease9.Complications of rheumatic heart disease10.Cyanosis: causes and consequences11.Detecting alcohol abuse12.Discovery of circulation: Harvey film (TIMETABLE)13.Doctors' dilemmas: treating friends family14.Drug therapy for stable effort angina15.Essential Life Support16.Features of Down syndrome17.Flow and pressures in the circulation18.Functions of the heart as a pump19.Genesis of atheroma20.Gross and fine anatomy of blood vessels21.History of chronic fatigue syndrome22.Immune mechanisms in rheumatic fever23.Lifestyle modification in vascular disease24.Long term management of childhood cardiac disease25.Medicolegal issues in information-giving26.Microbiology of endocarditis and rheumatic heart disease27.Normal ECG28.Oedema29.Overview of cardiovascular function30.Overview of congenital heart disease31.Pathogenesis of hypertension32.Pathophysiology of hypertension33.Pathophysiology of ischaemia34.Personality and coronary heart disease35.Pregnancy and cardiovascular system36.Prenatal Diagnosis and Down Syndrome37.Regulation of cerebral blood flow38.Short term regulation of blood pressure39.Social roles: responses to health and illness40.Structure of heart and great vessels41.Support for carers42.Syncope43.The foetal circulation44.Treatments for hypertension45.Ventricular arrhythmias46.

LEARNING TOPIC - Activation of the heart

Activation of the heart includes

all the processes which determine and regulate the heart ratethe way in which electrical activity spreads across the heartthe processes which link electrical activity in the individual cardiac cells to their contraction.

Important clinical topics which depend on these concepts are the electrocardiogram and arrhythmias.

The pacemakers

The heart rate is determined by the activity of small regions of spontaneously excitable tissue known aspacemakers. Just as in other excitable tissues the electrical activity is a depolarisation of the membrane potential

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Activation of the heart includes

all the processes which determine and regulate the heart ratethe way in which electrical activity spreads across the heartthe processes which link electrical activity in the individual cardiac cells to their contraction.

Important clinical topics which depend on these concepts are the electrocardiogram and arrhythmias.

The pacemakers

The heart rate is determined by the activity of small regions of spontaneously excitable tissue known aspacemakers. Just as in other excitable tissues the electrical activity is a depolarisation of the membrane potentialknown as the action potential. The activity of these pacemakers is modified by the autonomic nervous system;this is the mechanism by which the heart rate increases when we are frightened and decreases during sleep. Youneed to be familiar with

the name, intrinsic rate and site of the primary, secondary and tertiary pacemakersbe able to draw the action potential from a pacemaker cell and show how sympathetic transmittersaccelerate the heart rate and parasympathetic transmitters slow the heart rateknow the normal heart rate, the range over which it can change and the consequences for cardiac functionif you like more biophysical problems, understanding the currents which lead to spontaneous cyclicalactivity is a fascinating issuestart to think about what will happen if one or other of the pacemaker stops working or goes too fast or tooslow (not many clocks run for 70 years without any problems and the heart is no exception).

The spread of electrical activity

The principle is that the primary pacemaker in the sinoatrial node determines the heart rate and the electricalactivity then spreads over the heart. For mechanical reasons the atria and the ventricles both need to contractmore or less synchronously whereas, because atrial contraction assists filling of the ventricles, it is important thatatrial contraction precedes ventricular contraction. To understand these issues, which are essential tounderstanding the electrocardiogram, you need to be able to

describe and draw a diagram of the pathway by which electrical activity spreads over the heartdraw a table showing the parts of the pathway, their intrinsic rate if spontaneously active, the velocity ofconduction and the approximate delaystart to think about how all this leads to the electrocardiogram (a difficult issue unless you are an electricalengineer used to describing currents in 3 dimensional space).

Excitation-contraction coupling

When the action potential gets to the individual myocytes it causes them to contract. Because the heart needs tovary its force of contraction to get big or small outputs as required it has developed a method for varying theforce of contraction. Thus when the heart rate increases, or when the heart is stimulated, or when various drugsare used, the force of every cell increases via the sympathetic nervous system. You need to know

the appearance of a typical ventricular action potentialhow does the action potential trigger contraction in cardiac cellshow is it that the mechanism is variablehow drugs such as adrenaline or the cardiac glycosides lead to increased force.the appearance of a typical pacemaker action potential

References

Use the textbooks in your Tutorial Room

Optional references:Available in Medical Library: see Library Catalogue

Sherwood, L., 2007, Human physiology : from cells to systems, 6th ed., Thomson/Brooks/Cole, Australia

Berne, R. M., 2004, Physiology, 5th ed., Mosby, St. Louis.

Guyton, A. C. and J. E. Hall, 2006, Textbook of medical physiology, 11th ed., Elsevier Saunders, Philadelphia. .

Author: Professor David G Allen, Physiology

LEARNING TOPIC - Assessing peripheral vascular disease

Peripheral Vascular Disease is a term used to describe symptomatic chronic arterial occlusion, usually in the lowerlimbs. It is a disease that usually follows a slowly progressive course from intermittent pain on walking toconstant severe pain, ulceration, gangrene and limb loss.


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LEARNING TOPIC - Assessing peripheral vascular disease

Peripheral Vascular Disease is a term used to describe symptomatic chronic arterial occlusion, usually in the lowerlimbs. It is a disease that usually follows a slowly progressive course from intermittent pain on walking toconstant severe pain, ulceration, gangrene and limb loss.

The assessment of peripheral vascular disease is primarily a clinical task based on a careful history and physicalexamination. Muscle pain (intermittent claudication) is the principal symptom.

In the early stage of the disease the pain is due to ischaemia of exercising muscle groups, most commonly thecalf muscles on running or walking, though depending on the anatomical distribution of the arterial occlusivedisease, other sites such as the buttock muscles or thighs may be the first to cause pain.

The arterial disease is usually due to atherosclerosis, and the pain typically fades away when the patient rests forseveral minutes, allowing the flow of oxygenated blood to better match the needs of the muscles to return toaerobic metabolism. At the same time, the blood pressure in the arteries distal to the obstruction, having fallen inparallel with the onset of pain, rises again to the pre-exercise levels as the blood flow catches up with themetabolic requirements of the vascular bed.

As the disease becomes more severe, pain may appear at rest and at this stage is largely due to ischaemia ofperipheral nerves. The patient may notice altered sensation in the feet and toes, worse after walking, and burningnumbness may become the dominant symptom as the nerves are subjected to constant ischaemia. The rest painis worse at night and may be relieved for short periods by getting up and walking around. Finally, tissue losssecondary to minor trauma, infection or ischaemic gangrene completes the clinical course.

Clinical assessment of the new patient may be the only step required before commencement of treatment. Thenature of the pain is best confirmed by walking with the patient until the pain appears, and the examinationrepeated then. Careful physical examination including palpation and auscultation of the arterial tree of the lowerlimbs will demonstrate the level of the more proximal arterial occlusion or stenosis and. This is most commonly inthe femoro-popliteal arterial segment. Indeed this is often the only artery blocked in the patient who presentswith intermittent claudication.

Only by clinical or laboratory tests to define vessel patency at lower levels will the full extent of the occlusivedisease be revealed. Such tests must be considered in the severe claudicant and is always needed in the patientwith rest pain, who often has limb-threatening ischaemia. The presence or absence of flow in these distalsegments may be determined simply by the use of continuous wave Doppler examinations, usually withsegmental measurements of the systolic arterial pressure down the limb. Such Doppler pressure studies are mostinformative and accurate when coupled with treadmill exercise, with systolic measurements performed before andafter exercise until the ankle arterial pressure returns to the pre-excise level. These may be compared with thebrachial artery systolic pressure to generate a ratio called the ankle/brachial index.

Other forms of assessment will demonstrate patent arterial segments (angiography by direct femoral puncture orvia intra-arterial catheters) or flow in open vessels (arterial duplex scanning of the lower limb arteries).Angiography remains the most useful investigation before surgical intervention, which may be either radiological,endoscopic or open. Arterial duplex studies are non-invasive and almost as accurate as arteriography and havethe additional advantage of being able to assess flow velocities to determine whether an arterial stenosiscontributes significantly to the symptomatic limitation of flow. Such studies may also better define the patientwho would benefit from angiographic interventional treatment, either balloon angioplasty or angiographicstenting.

References



Burkitt, H. G. and C. Quick, 2002, Essential surgery : problems, diagnosis, and management, 3rd ed., ChurchillLivingstone, Edinburgh. Pages 459- 462 (Acute lower limb ischaemia)

Lawrence, P. F., et al., 2006, Essentials of general surgery, 4th ed., Lippincott Williams & Wilkins, Philadelphia

White, R. A. and L. H. Hollier, 1994, Vascular surgery : basic science and clinical correlationsed., Lippincott,Philadelphia.

Dormandy J, Maher M, Ascardy G et al. Fate of the patient with chronic leg ischaemia. J Cardiovasc Surg 1989;30(1): 50-57.

Peabody NC, Kannel WB, McNamara PM. Intermittent Claudication: Surgical Significance. Arch Surg 1974; 109(5):693-696.


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Burkitt, H. G. and C. Quick, 2002, Essential surgery : problems, diagnosis, and management, 3rd ed., ChurchillLivingstone, Edinburgh. Pages 459- 462 (Acute lower limb ischaemia)

Lawrence, P. F., et al., 2006, Essentials of general surgery, 4th ed., Lippincott Williams & Wilkins, Philadelphia

White, R. A. and L. H. Hollier, 1994, Vascular surgery : basic science and clinical correlationsed., Lippincott,Philadelphia.

Dormandy J, Maher M, Ascardy G et al. Fate of the patient with chronic leg ischaemia. J Cardiovasc Surg 1989;30(1): 50-57.

Peabody NC, Kannel WB, McNamara PM. Intermittent Claudication: Surgical Significance. Arch Surg 1974; 109(5):693-696.

Currie I, Wilson Y, Baird R, Lamont P. Treatment of Intermittent Claudication: The impact on quality of life . Eur JVasc Endovasc Surg 1995; 10(3):356-361.

Author: Associate Professor Peter Thursby, Surgery

LEARNING TOPIC - Atrial fibrillation

Atrial fibrillation (AF) is the most common of the cardiac arrhythmias. The prevalence increases with age, and2-5% of those older than 60 have AF. AF may be paroxysmal or chronic. Paroxysmal episodes of AF often precedechronic (permanent) AF.

AetiologyMost types of heart disease can cause AF. The most important associations are mitral valve disease, hypertensiveheart disease, ischaemic heart disease, thyrotoxicosis, cardiomyopathy and idiopathic (lone fibrillation). In theweek following open heart surgery, 20 to 30% of patients experience transient AF.

MechanismAF is caused by multiple wandering wavelets of re-entry within the atria. Approximately 6 wavelets are requiredfor the development of sustained AF. The mechanism by which heart disease causes this phenomenon isuncertain. It is probable that high atrial pressures lead to stretching of the atrium and atrial damage, this in turncauses fibrosis which promotes the development of re-entrant circuits.

Not every impulse from the rapidly beating atria is conducted to ventricles. The AV node is bombarded randomlyby impulses, and only a proportion of these are conducted to the ventricles. Thus the ventricles contractirregularly. In untreated AF the ventricular rate is usually between 150 and 200 beats per minute. If this rapidrate continues for several days or if the patient has significant valvular or myocardial disease, the patient soondevelops cardiac failure.

SymptomsThe most common symptom of AF is that of rapid irregular palpitations. The patient may also feel fatigued. Ifheart failure develops the patient may experience dyspnoea, ankle swelling and abdominal distension.

SignsThe pulse and heart beat are rapid and irregularly irregular. If the heart contracts rapidly several times insuccession, there will be insufficient time for cardiac filling, and each contraction will not generate a significantpulse. Thus the pulse rate may be significantly lower than the heart rate. This is known as the 'pulse deficit'. Inaddition, signs of cardiac failure may be present and one might find signs of the causative condition such as mitralvalve disease or thyrotoxicosis.

DiagnosisAF is diagnosed on the electrocardiogram. P waves are absent and instead a finely undulating baseline is present.These are known as fibrillation waves and have a frequency of 350-600 beats per minute. QRS complexes occurirregularly with an average rate of 150 to 200 beats per minute in untreated AF.

ComplicationsTwo major complications of AF are heart failure and embolism. Heart failure develops because of the rapidventricular rate. Lack of effective atrial contraction may also contribute.

Embolism may occur because the atrial contractions are feeble during AF, and this allows pockets of stasisparticularly in the left atrial appendage. This promotes thrombosis. Thrombi may detach themselves and lodge inthe systemic circulation.

TreatmentSeveral methods are used to treat AF. It is important to treat the cause of the atrial fibrillation, eg thyrotoxicosis,valvular or hypertensive heart disease. Methods of treatment include drug treatment and DC cardioversion.

Drug TreatmentTwo strategies are used to treat AF. The first is to control the ventricular rate. This is done by increasing thedegree of block in the AV node. Drugs which are used for rate control include digoxin, verapamil and beta


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ventricular rate. Lack of effective atrial contraction may also contribute.

Embolism may occur because the atrial contractions are feeble during AF, and this allows pockets of stasisparticularly in the left atrial appendage. This promotes thrombosis. Thrombi may detach themselves and lodge inthe systemic circulation.

TreatmentSeveral methods are used to treat AF. It is important to treat the cause of the atrial fibrillation, eg thyrotoxicosis,valvular or hypertensive heart disease. Methods of treatment include drug treatment and DC cardioversion.

Drug TreatmentTwo strategies are used to treat AF. The first is to control the ventricular rate. This is done by increasing thedegree of block in the AV node. Drugs which are used for rate control include digoxin, verapamil and betablockers.

The second strategy is to give drugs to revert the AF and thereafter to decrease the frequency of furtherepisodes. Drugs used for this purpose include sotalol, amiodarone and flecainide.

DC CardioversionIf a patient is severely compromised with AF, an alternative treatment is DC cardioversion (DC shock to thepraecordium designed to revert the arrhythmia).

AnticoagulationAF significantly increases the risk of systemic embolism and embolic stroke. The risk of stroke depends on thetype of heart disease causing the AF. In patients with rheumatic valve disease and AF, the incidence of stroke isincreased between 15 and 20 times above that of the general population but patients with AF and no heartdisease do not have an increased risk of stoke. Treatment with warfarin is effective, but carries an increased therisk of bleeding. The risk of serious thromboembolism in patients with AF is about 5% per year. Warfarindecreases this risk to about 1% per year. The risk of serious haemorrhage whilst taking warfarin is < 1% peryear. Patients with lone AF are not given warfarin. Aspirin has also been used to decrease the risk ofthromboembolism but is only about 25%-50% as effective as warfarin.

Curative ProceduresA number of curative procedures have been developed to control AF. The most effective is the 'maze' procedure.This is an 'open-heart' surgical procedure in which a number of incisions are placed in the atria to create lines ofblock so that the multiple reentrant circuits cannot develop. This procedure is not widely performed because ofthe discomfort and risk posed by open-heart surgery. Several catheter ablation techniques have also beendeveloped but currently these are regarded as investigational since the safety and efficacy have not yet beendetermined.

AV Nodal Ablation and Implantation of PacemakerIn some patients with AF the ventricular rate remains high despite drug therapy. In these patients the ventricularrate may be controlled by intentionally destroying the AV node using catheter ablation techniques. A pacemakermust be implanted to treat the resulting bradycardia. Since the atria continue to fibrillate, anticoagulation mustbe continued after this procedure.

References


Author: Clinical Associate Professor Mark Mcguire, Medicine

LEARNING TOPIC - Causes of heart failure

Heart failure can be defined as the inability of the heart to maintain a cardiac output appropriate to systemicmetabolic requirements. Heart failure may be a low output state, where forward pump function of the heart isimpaired and cannot meet normal metabolic needs, or more rarely, a high output state, where pump function ofthe heart is normal but systemic metabolic needs are excessive. Examples of low output failure include impairedpump function due to cardiomyopathy or myocardial infarction. Examples of high output failure includethyrotoxicosis and beri-beri.

Heart failure is usually a chronic condition, but in some circumstances may be acute, as in acute valvularregurgitation. In chronic heart failure, the heart adapts and remodels in an attempt to compensate. Thisremodelling includes ventricular dilatation and eccentric myocardial hypertrophy. In acute heart failure,ventricular dilatation does not have time to develop and the major compensation is an increase in heart rate.

In a patient presenting with heart failure, it is important to distinguish between the underlying cause and theimmediate precipitating cause. The underlying cause is the pathological process affecting the heart and leading toimpaired myocardial pump function. A precipitating cause is a factor or event which results in decompensation ofthe heart and symptoms. Typical precipitating causes are factors placing an additional load upon the heart suchas fever, anaemia or systemic infection. In addition, arrhythmias such as atrial fibrillation, may precipitate overtheart failure.


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Heart failure is usually a chronic condition, but in some circumstances may be acute, as in acute valvularregurgitation. In chronic heart failure, the heart adapts and remodels in an attempt to compensate. Thisremodelling includes ventricular dilatation and eccentric myocardial hypertrophy. In acute heart failure,ventricular dilatation does not have time to develop and the major compensation is an increase in heart rate.

In a patient presenting with heart failure, it is important to distinguish between the underlying cause and theimmediate precipitating cause. The underlying cause is the pathological process affecting the heart and leading toimpaired myocardial pump function. A precipitating cause is a factor or event which results in decompensation ofthe heart and symptoms. Typical precipitating causes are factors placing an additional load upon the heart suchas fever, anaemia or systemic infection. In addition, arrhythmias such as atrial fibrillation, may precipitate overtheart failure.

There are many potential underlying causes of heart failure, which should be sought in patients who present withsymptoms of heart failure. These causes include impaired blood supply due to coronary artery disease, with orwithout myocardial infarction, and increased haemodynamic load on the heart due to valve disease, such as aorticstenosis or aortic or mitral regurgitation. Often heart failure is due to an intrinsic dysfunction of the systoliccontractile function of the myocardium, known as a cardiomyopathy, and this results in dilatation of the cardiacchambers. Causes of dilated cardiomyopathy include alcohol abuse, previous myocarditis, hereditary defects inmyocardial metabolism and metabolic abnormalities such as hyper/hypo-thyroidism, or haemochromatosis.Occasionally drugs or heavy metal poisoning can cause cardiomyopathy. An important drug cause is theanti-cancer drug, adriamycin.

A less common cause of heart failure is a restrictive cardiomyopathy. These patients typically have thickened andstiff ventricular myocardium, due to fibrous infiltration or deposition of abnormal glycoproteins. The most commoncause in Australia is amyloidosis which is manifest mostly in older women. In patients presenting with heartfailure it is important to look for the precipitating cause as this may be readily treatable and can result in rapidclinical improvement for the patient. It is also important to look for the underlying cause of heart failure, as thismay be reversible in some cases, such as by coronary artery bypass grafting in coronary artery disease or bystopping alcohol intake.

References



Kumar, V., et al., 2005, Robbins and Cotran pathologic basis of disease, 7th ed., Elsevier Saunders, Philadelphia.[Available as a E-Book]

Boon, N. A. and S. Davidson, 2006, Davidson's principles & practice of medicine, 20th ed., Elsevier/ChurchillLivingstone, Edinburgh ; New York.

Author: Professor Richmond Jeremy, Medicine

LEARNING TOPIC - Causes of tiredness

Tiredness is a very common presentation in medical practice, comprising 5-10% of all presentations in generalpractice. Although the cause is usually found to be psychological or social in nature (in 50-80% of cases), anover-riding initial concern is to exclude physical causes requiring treatment.

Psychosocial factors

Most people presenting to their doctor with tiredness will have a psychosocial cause, and most of those people willhave associated features of depression (e.g. insomnia, morning tiredness, loss of interest, poor self esteem) oranxiety (e.g. worry, apprehension, or irritability). Depression is very common and should always be consideredand excluded by specific questioning. Anxiety is often related to lifestyle (e.g. relationships, family, work,financial), and this can usually be identified by empathic inquiry.

Physical causes

Almost any medical condition can cause tiredness, but certain medical conditions cause persistent tiredness as amajor manifestation. These conditions usually have associated symptoms and signs which should be sought bycareful initial history and physical examination. The most common associated symptoms (and conditions) include:weight loss (malignancy, chronic infection, diabetes, hyperthyroid), polydipsia, polyuria (diabetes), fever(infection, malignancy), cold intolerance (hypothyroidism), melaena or menorrhagia (anaemia), amenorrhoea,nausea and mastalgia (pregnancy), hypertension and/or dyspnoea (heart failure), snoring and/or daytimesomnolence (sleep apnoea).

Infections which commonly cause persistent tiredness include: infectious mononucleosis, HIV, hepatitis C,tuberculosis, subacute bacterial endocarditis (SBE).


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Physical causes

Almost any medical condition can cause tiredness, but certain medical conditions cause persistent tiredness as amajor manifestation. These conditions usually have associated symptoms and signs which should be sought bycareful initial history and physical examination. The most common associated symptoms (and conditions) include:weight loss (malignancy, chronic infection, diabetes, hyperthyroid), polydipsia, polyuria (diabetes), fever(infection, malignancy), cold intolerance (hypothyroidism), melaena or menorrhagia (anaemia), amenorrhoea,nausea and mastalgia (pregnancy), hypertension and/or dyspnoea (heart failure), snoring and/or daytimesomnolence (sleep apnoea).

Infections which commonly cause persistent tiredness include: infectious mononucleosis, HIV, hepatitis C,tuberculosis, subacute bacterial endocarditis (SBE).

The use of prescribed and non-prescribed drugs (for example, alcohol, B-blockers, anticonvulsants, anxiolyticsand NSAIDS) can cause tiredness and should be carefully sought in the history.

Physiological tiredness, due to excessive physical or psychological activity is common in day to day life, butuncommon in medical practice. The cause is usually obvious (sometimes to everyone except the affected person),although physical and psychological causes must first be excluded in the history and examination. Inquiry shouldcentre on day to day patterns of work, rest and recreation.

Chronic fatigue syndrome should be considered in patients with fatigue lasting longer than six months in whomother diseases have been excluded.

References



Murtagh, J., 2007, John Murtagh's general practice, 4th ed., McGraw-Hill Australia, Sydney

A good comprehensive introduction to the diagnosis and management of a patient presenting with fatigue.

McWhinney, I. R., 1997, A textbook of family medicine, 2nd ed., Oxford University Press, New York

A useful supplement to Murtagh. Emphasises a diagnostic approach to presentations of fatigue in general practice.Useful recent journal articles:

Dick ML, Sundin J. Psychological and psychiatric causes of fatigue. Assessment and management. AustralianFamily Physician 2003;32(11):877-881.

Murtagh J. Fatigue : a general diagnostic approach. Australian Family Physician 2003;32(11):873-876.

Murdoch JC. Chronic fatigue syndrome. The patient centred clinical method--a guide for the perplexed. Aust FamPhysician. 2003;32(11):883-887.

Author: Professor Simon Willcock, General Practice

LEARNING TOPIC - Chromosomal abnormalities and early development in Down syndrome

The human chromosome complement was established as recently as 1956 as 23 pairs, i.e. 46 chromosomes. Thisis called the diploid number of chromosomes. Down syndrome was the first disorder in which a chromosomeabnormality was discovered by Lejeune and colleagues in 1958. They established that the majority (95%) ofDown syndrome subjects had an additional 21 chromosome. More sophisticated cytogenetic techniques revealthat a variety of different chromosomal mechanisms result in Down syndrome although these all share thecommon abnormality of triplication of chromosome 21 genes.

Cytogenetic Mechanisms Responsible for Down Syndrome

Trisomy 21 95 %

Translocation 2.5%


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is called the diploid number of chromosomes. Down syndrome was the first disorder in which a chromosomeabnormality was discovered by Lejeune and colleagues in 1958. They established that the majority (95%) ofDown syndrome subjects had an additional 21 chromosome. More sophisticated cytogenetic techniques revealthat a variety of different chromosomal mechanisms result in Down syndrome although these all share thecommon abnormality of triplication of chromosome 21 genes.

Cytogenetic Mechanisms Responsible for Down Syndrome

Trisomy 21 95 %

Translocation 2.5%

Mosaicism 2.5%

Other <1%

What are the Mechanisms which Produce Trisomy 21

During meiosis (the formation of germ cells), the chromosome complement is halved to 23. This is called thehaploid number. There are 2 steps, Meiosis I in which the diploid number is halved to 23, and Meiosis II in whichthe chromosomes are replicated similar to a mitotic step. Non-disjunction, i.e. the non-segregation of pairedsister chromosomes to 2 daughter cells, results in a germ cell with 24 chromosomes and a corresponding germcell with 22 chromosomes.

Molecular Cytogenetic and DNA polymorphism studies demonstrate that the error occurs in maternal meiosis I in75% and meiosis II in 25% of patients. When the error occurs in paternal meiosis the ratios are reversed meiosisI (25%) and II (75%). Epidemiologic studies show that an increased incidence of trisomy 21 Down syndrome isstrongly connected with the maternal age >37 years. Errors occur in meiosis in women at all ages. At 40 years,the incidence of Down syndrome is approximately 1:100 compared with an incidence of 1:1000 in women 29years.

Translocation

Physical fusion of two chromosomes (or part of chromosomes) is known as translocation. This anomaly may bestably inherited. Fusion between chromosomes which have their centromere at one end (acrocentrics) i.e.chromosomes 13, 14, 15, 21 and 22 are known as Robertsonian translocations. A Robertsonian translocationwhich does not affect the absolute number (dosage) of chromosome 21 causes no phenotypic effects. Balancedtranslocations may be stably inherited. However balanced translocations result in abnormal pairing at meiosis andin gametes with an unbalanced composition (excess or insufficiency). Unbalanced Robertsonian translocation isresponsible for 2-3% of Down syndrome, in which half those affected are inherited. Recurrence risks vary. The21;21 translocation when present in a parent results in 100% Down syndrome offspring (the monosomicconceptus is previable lethal).

Mosaicism

About 2.5% of patients have a mixture of body cells, normal cells with 46 chromosomes and Down syndrome cellswith 47 chromosomes. There is a wide variation in intellectual disability (if any) and phenotypic effects. Someindividuals with Down syndrome mosaicism commence life as full trisomic embryos but one 21 is lost by anaphaselag in early embryogenesis. This is sometimes known as “trisomic rescue”.

Other

Patients have been described with partial trisomy (duplication) for a region of the long arm of chromosome 21.The region of chromosome 21, 21q 22.13-22.2 is responsible for most of the phenotype. Partial trisomy may beundetectable by standard methods of chromosomal (cytogenetic) analysis such as G banding and Fluorescence insitu hybridisation (FISH) employing probes for a region of chromosome 21. Tiny duplications may be detected byinterphase FISH and Comparative Genomic Hybridisation Array technology (CGH array) (Ronan et al 2007).

References


Optional references:

Antonarakis S, Lyle R, Dermitzakes ET, Reymond A, Deutsch S. Chromosome 21 and Down Syndrome: fromgenomics to pathophysiology . Nature Reviews Genetics 2004; 5(10):725-737.

Gardner, R. J. M. and G. R. Sutherland, 2004, Chromosome abnormalities and genetic counseling, 3rd ed., OxfordUniversity Press, New York. Pages 249-263


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References



Antonarakis S, Lyle R, Dermitzakes ET, Reymond A, Deutsch S. Chromosome 21 and Down Syndrome: fromgenomics to pathophysiology . Nature Reviews Genetics 2004; 5(10):725-737.

Gardner, R. J. M. and G. R. Sutherland, 2004, Chromosome abnormalities and genetic counseling, 3rd ed., OxfordUniversity Press, New York. Pages 249-263

Patterson D, Costa AC. Down syndrome and genetics - a case of linked histories . Nature Reviews Genetics 2005Feb; 6(2):137-47.

Ronan A, Fagan K, Christie L, Conroy J, Nowak NJ and Turner G. Familial 4.3 Mb duplication of 21q22 sheds newlight on the Down syndrome critical region. J. Med. Genet. 2007 44(7):448-51.

Author: Professor David Sillence, Genetic Medicine

LEARNING TOPIC - Chronic viral infections

Many viruses establish long-term relationships with their human hosts, and everyone carries a substantial numberwhich have little impact on their health.

The mechanisms allowing them to achieve persistence vary. Some, such as the herpes viruses which cause coldsores chicken pox and glandular fever, produce an acute infection with a vigorous host response, but thenbecome latent. During acute infection they produce progeny virus and kill their host cells, but during latency onlyone or two viral genes are transcribed. Such viruses can be reactivated and may then cause quite a differentdisease picture (compare chicken pox with shingles, glandular fever with Burkitt's lymphoma).

Viruses from some other taxonomic groups cause little acute disease, but evade the host response and continueto replicate and cause on-going cell damage in their target organ. Hepatitis C and HIV are good examples of thisgroup. They characteristically mutate to form 'quasi-species' in response to immune pressure.

Yet another group of chronic viral diseases are caused by persistence of defective virus in the tissues. Subacutesclerosing panencephalitis following measles and squamous carcinoma due to papillomavirus are two famousexamples.

These mechanisms are not mutually exclusive For instance hepatitis B and papillomaviruses may use two or evenall three. Many examples of chronic virus infection (such as cytomegalovirus) have come to notice in immunedeficient patients and cause major problems in their management. Unrestrained viral replication produces severetissue injury and also high levels of infectivity to contacts. Some viruses, such as poliomyelitis and humanparvovirus which are eliminated by normal people, become chronic in the immune deficient.

Chronic viral infections may

cause apparently acute illness, particularly by reactivationlead to 'non-communicable' diseases including malignancies (Burkitt's lymphoma and cancer of the cervixfor example ) and degenerative CNS syndromes (eg progressive multifocal leucoencephalopathy (PML) ,tropical paraparesis)produce continuing long-term damage to their target organ, either directly or by inducing immunologicaldestruction of infected cells

Recognition of the large number and variety of chronic virus infections has led to attempts to implicate them innumerous 'non-infectious' syndromes. Theses especially include degenerative diseases of the CNS such asmultiple sclerosis and malignancies including lymphomas and cancer of the breast. Animal diseases often provideclues in making such disease associations, but most remain controversial and unproved.

Chronic viral infections also induce on-going production of lymphokines such as interferon, and lymphocyteproliferation may also be found. Non-specific symptoms, particularly fatigue, muscle aches and low grade fevermay result. Fatigue may be the presenting symptom in patients with cumulative tissue damage, eg hepatitis C orHIV, but the clinical association of fatigue with viruses which are carried by most healthy people is difficult toprove either for individual patients or the community. Molecular techniques continue to reveal 'new' viruses (egHHV6, HHV8, and hepatitis G) which cause chronic infection, but whose disease load is still very uncertain. Aseach is discovered renewed attempts are made to associate virus infections with these unexplained syndromes.

The control of chronic viral infections is difficult because asymptomatic people are likely to remain infectious formany years and treatment regimes, if available, are very long term.

References



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proliferation may also be found. Non-specific symptoms, particularly fatigue, muscle aches and low grade fevermay result. Fatigue may be the presenting symptom in patients with cumulative tissue damage, eg hepatitis C orHIV, but the clinical association of fatigue with viruses which are carried by most healthy people is difficult toprove either for individual patients or the community. Molecular techniques continue to reveal 'new' viruses (egHHV6, HHV8, and hepatitis G) which cause chronic infection, but whose disease load is still very uncertain. Aseach is discovered renewed attempts are made to associate virus infections with these unexplained syndromes.

The control of chronic viral infections is difficult because asymptomatic people are likely to remain infectious formany years and treatment regimes, if available, are very long term.

References



Look up the viruses listed above in Mims [Available as an E-book] and compare the mechanisms andmanifestations of acute and chronic infection for each.

Mandell, G. L., R. G. Douglas, et al., 2005, Mandell, Douglas, and Bennett's principles and practice of infectiousdiseases, 6th ed., Elsevier/Churchill Livingstone, New York. [Available as an E-Book]

Author: Professor Peter McMinn, Infectious Diseases

LEARNING TOPIC - Clinical and laboratory assessment in heart failure

The assessment of a patient with heart failure is directed towards determining both the severity and the cause ofheart failure. Clinical assessment is based upon the patient's symptoms, including dyspnoea, orthopnoea, fatigueand exercise tolerance. The severity of clinical symptoms can be graded according to criteria of the New YorkHeart Association, from Class 1 (mild symptoms) to Class 4 (severe restriction of activity). The NYHA Class is animportant prognostic indicator as well as a useful description of the patient's functional status. The clinicalassessment also includes physical examination with emphasis upon the signs of heart failure, including peripheraloedema, elevation of the jugular venous pressure, displacement of the apex beat of the heart and auscultatorysigns such as atrial or ventricular gallop sounds and murmurs of aortic or mitral regurgitation. Clinical assessmentusually reveals the severity of the patient's heart failure and may reveal the underlying cause, such as a historyof myocardial ischaemia, or physical signs of chronic liver disease and alcohol abuse.

Simple investigations can provide further information. The electrocardiogram may reveal previous myocardialinfarction or signs of left ventricular hypertrophy or document an arrhythmia (eg atrial fibrillation). The chestX-ray provides an indication of cardiac size and is important for assessment of pulmonary congestion, withevidence of upper lobe venous distension or interstitial oedema. Biochemical tests are directed towards evaluatingconsequences of heart failure (ie blood electrolytes and creatinine) and also towards possible causative factors,such as anaemia (full blood count), alcohol abuse (liver function tests), endocrine abnormalities (thyroid functiontests).

In many cases, the physician will seek to document the degree of impairment of cardiac function. This entailscardiac imaging, usually by echocardiography or equilibrium radionuclide ventriculography. These imaging studiesprovide information about cardiac size and pump function, which is often quantitated by the ejection fraction(ejection fraction = strake volume/end-diastolic volume). The normal adult left ventricular ejection fraction is50-70%. In general, patients with an ejection fraction below 25% have severe heart failure.

In specific circumstances, other more specialised investigations may be required, such as myocardial perfusionscanning with radionuclides or coronary angiography to detect coronary artery disease. It is to be emphasisedthat heart failure is not a diagnosis in itself, but rather a symptom complex indicative of cardiac disease. It istherefore necessary to undertake an appropriate clinical and investigative assessment to define the severity andcauses of heart failure in order to rationally plan treatment for the patient which can relieve symptoms and mayeven restore cardiac pump function in certain cases.

References






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LEARNING TOPIC - Complications of ischaemic heart disease

The major complication of coronary artery disease is myocardial infarction. This results from thrombotic occlusionof a major coronary artery. In patients who develop myocardial infarction, a number of serious complications mayfollow, either acutely or in the healing phase. These include:-

Arrhythmias:

In the acute stages, conduction disturbances may result from infarcts which involve the conduction system andusually produce bradyarrhythmias while tachyarrhythmias result from myocardial irritability or re-entry.Transmural infarcts in the posterior wall of the left ventricle are especially likely to lead to bradyarrhythmias. Inthe convalescent phase and late after infarction, ventricular tachcardia and fibrillation result from reentry aroundthe edges of scar, and are a major cause of sudden death.

Left ventricular dysfunction:

This may lead to left-sided cardiac failure, pulmonary congestion and oedema. A large, transmural infarctinvolving 40% of the left ventricular wall or more may be followed by profound ventricular dysfunction, acute"pump failure" and cardiogenic shock.

Rupture of the myocardium:

Infarcted myocardium undergoes softening especially during the acute inflammatory response to the necrosis.This can lead to its rupture in the following locations:

The free or external ventricular wall. Haemopericardium will result from escape of blood from the leftventricle.The interventricular septum. Shunting of blood between the ventricles usually left to right, occurs.The papillary muscle with acute onset of mitral regurgitation. Papillary muscle dysfunction may result fromischaemia without rupture of the muscle. Rupture of the papillary muscle leads to sudden onset mitralregurgitation, and may be heralded by acute pulmonary oedema.

Mural thrombosis:

This occurs most frequently in the left ventricle, and is caused by stasis of blood due to ventricular hypokinesis orendocardial injury in the area of infarction. Such thrombus may embolise into the systemic circulation withpossible impaction for example in a cerebral vessel.

Patients with myocardial infarction are at high risk of development of hypercoagulability of blood. They arepredisposed to the development of deep venous thrombosis and pulmonary embolism.

The propensity toward certain complications depends greatly on the proportion of the myocardial wall damagedby infarction. As noted above, patients with large transmural infarcts tend to be more susceptible to developarrhythmias and shock while a transmural infarct of the free wall may rupture more readily.

Mostly, myocardial infarction will commence in the subendocardial region which is the least well-perfused part ofthe myocardium. However within a few hours, this infarct can progress along a wavefront of necrosis to becometransmural. This wavefront necrosis may be modified by prompt thrombolysis and coronary reperfusion.

Patients with transmural myocardial infarction in particular may develop an acute fibrinous pericarditiswithin a few days of occurrence of the infarctionInfarct extension. The zones bordering an area of recent infarction while still viable, may exhibit changes ofsublethal injury reflecting a lesser degree of ischaemic injury. These zones are unstable due to ischaemiaand in the days or weeks following the original infarct there may be extension of necrosis into theseadjoining areas.Cardiac remodelling. In some patients, myocardial infarction is followed by a series of changes involvingboth the area of infarction and the adjoining wall and culminating in a change in ventricular shape anddimensions. This involves infarct expansion which begins as early as within 24 hours after occurrence ofinfarction and in which the area of infarction undergoes disproportionate stretching and thinning. Thisdiffers from infarct extension in that further necrosis is not a prerequisite. A similar but less pronouncedthinning and dilatation occurs in the adjoining non-infarcted region. It has been shown that most of thethinning in the infarcted region and all of the thinning in the non-infarcted zone is due to rearrangement of


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Infarct extension. The zones bordering an area of recent infarction while still viable, may exhibit changes ofsublethal injury reflecting a lesser degree of ischaemic injury. These zones are unstable due to ischaemiaand in the days or weeks following the original infarct there may be extension of necrosis into theseadjoining areas.Cardiac remodelling. In some patients, myocardial infarction is followed by a series of changes involvingboth the area of infarction and the adjoining wall and culminating in a change in ventricular shape anddimensions. This involves infarct expansion which begins as early as within 24 hours after occurrence ofinfarction and in which the area of infarction undergoes disproportionate stretching and thinning. Thisdiffers from infarct extension in that further necrosis is not a prerequisite. A similar but less pronouncedthinning and dilatation occurs in the adjoining non-infarcted region. It has been shown that most of thethinning in the infarcted region and all of the thinning in the non-infarcted zone is due to rearrangement ofmyocytes or "cell slippage" with a reduction in layers of myocytes in the ventricular wall.

As a result the ventricle dilates, its volume increases as do the stresses on its wall. Such patients have highermortality than those in whom remodelling is not observed because of development of congestive heart failure andventricular arrhythmias. It is believed that remodelling may be modified by treatment which reduces preload orafterload stress and that coronary reperfusion may also be beneficial.

Author: Dr Suchitra Chandar, Cardiology

LEARNING TOPIC - Complications of rheumatic heart disease

Rheumatic heart disease is the sequel to one or more attacks of acute rheumatic fever. In up to 50% of patientswith the condition there is no history of a documented episode of rheumatic fever, whereas a significantpercentage of those who have had rheumatic fever do not develop chronic rheumatic involvement of the heart,especially if the acute attack is accompanied by only mild carditis.

Chronic valvular disease is the most important consequence of rheumatic fever. The mitral valve is most oftenaffected, and it is unusual to have rheumatic heart disease in the absence of mitral involvement. Aortic valvedisease often co-exists with mitral valve disease and may be the predominant valve affected. Less often thetricuspid valve is also affected, although it is often functionally regurgitant. The affected valves may be eitherstenosed or regurgitant, and you should read how the heart responds to these mechanical lesions, how they canbe assessed by clinical examination and investigation (ECG, chest X-ray, echocardiogram and cardiaccatheterisation), and the indications for medical, balloon and surgical treatments.

Arrhythmias are a common complication of chronic rheumatic heart disease, with atrial fibrillation being the mostfrequently observed. This arrhythmia is most often seen in patients with mitral valve disease and left atrialdilatation due to chronic pressure and volume overload. The onset of atrial fibrillation is accompanied by a fastand irregular ventricular response, and treatment is directed towards control of the ventricular rate. The loss ofatrial systole and its effect on cardiac performance, and the increased risk of thrombo-embolism are the majoradverse complications of this arrhythmia. Your reading should be directed towards understanding thepathogenesis and treatment of patients with atrial fibrillation, including the drugs that are used to slow theventricular rate and the management strategy involved in re-establishing sinus rhythm.

Thrombo-embolism is a complication which particularly occurs in patients with mitral valve disease and atrialfibrillation. The most devastating consequence is embolic stroke. Life-long anticoagulation is the most importantprophylactic measure. The maintenance of sinus rhythm is another important treatment goal. Occasionally thethrombus which forms in the left atrium is so large that it obstructs the mitral valve orifice. Your reading shouldinclude the management of patients on long-term oral anticoagulation.

Infective endocarditis is a serious but often preventable complication of chronic valvular disease. Its presentationvaries from an acute rapidly progressive illness to a subacute more indolent condition. Your reading shouldinclude prophylactic measures, diagnosis of endocarditis and the medical and surgical treatment of the conditionand its complications.

Recurrent attacks of acute rheumatic fever are particularly prevalent in those countries where its prophylaxis issuboptimal. Prophylaxis includes public health measures, the prompt treatment of streptococcal upper respiratoryinfections, and the continuous antibiotic use up to the age of approximately 30 years in all individuals who havehad a documented attack of acute rheumatic fever. Recurrent episodes of rheumatic fever can produce furthervalve and myocardial damage. The latter can manifest later as impaired left ventricular function out of keepingwith the degree of valvular dysfunction. Your reading should include the aetiology, pathology and prevention ofacute rheumatic fever and its occurrences.

References



Zipes, D. P. and E. Braunwald, 2005, Braunwald's heart disease : a textbook of cardiovascular medicine, 7th ed.,


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had a documented attack of acute rheumatic fever. Recurrent episodes of rheumatic fever can produce furthervalve and myocardial damage. The latter can manifest later as impaired left ventricular function out of keepingwith the degree of valvular dysfunction. Your reading should include the aetiology, pathology and prevention ofacute rheumatic fever and its occurrences.

References



Zipes, D. P. and E. Braunwald, 2005, Braunwald's heart disease : a textbook of cardiovascular medicine, 7th ed.,W.B. Saunders, Philadelphia, Pa. [Available as an E-Book]

Kasper, D. L. and T. R. Harrison, 2005, Harrison's principles of internal medicine, 16th ed., McGraw-Hill, MedicalPub. Division, New York. [Available as an E-Book]

Additional detail on acute rheumatic fever

Zipes, D. P. and E. Braunwald, 2005, Braunwald's heart disease : a textbook of cardiovascular medicine, 7th ed.,W.B. Saunders, Philadelphia, Pa. [Available as an E-Book] Chapter 82 (Rheumatic diseases and thecardiovascular system)

Author: Clinical Associate Professor David Richmond, Medicine

LEARNING TOPIC - Cyanosis: causes and consequences

Cyanosis refers to an abnormal dusky blue discolouration of the skin and/or mucous membranes due to a higherthan normal concentration of deoxygenated or unsaturated haemoglobin (deoxyhaemoglobin) in the tissuecapillaries. Haemoglobin changes colour from red to blue as it unloads oxygen from the capillaries into thetissues. Normally, the high proportion of saturated haemoglobin in the capillaries of visible tissues imparts theusual pink colour while the veins draining these tissues appear blue. Cyanosis arises through two basicmechanisms; either 1) the arterial blood entering these capillaries is less saturated than normal or 2) thecirculation may be slowed so that more extraction of oxygen per gram of haemoglobin occurs, hence increasingthe concentration of deoxyhaemoglobin in the capillaries. Both mechanisms may operate together.

Cyanosis is classified as peripheral or central. When extremities appear blue but the warm buccal mucosa andconjunctivae appear pink it is usually due to slowing of the circulation causing peripheral cyanosis and this is mostoften associated with cold induced vasoconstriction. More important pathological causes of peripheral cyanosis arereduced circulation due to atheromatous or traumatic narrowing of arteries (eg diabetic vasculopathy) orabnormal arterial spasm (eg Raynaud's phenomenon). Central cyanosis affecting the warm mucous membranes ismore important because this usually implies mechanism 1) above and this means that the systemic arterial bloodperfusing the whole body is deficient in oxygen. It is essential to appreciate that, by the time cyanosis isdetectable, the oxygen deficiency (hypoxaemia) in the arterial blood is very severe and potentially lifethreatening, particularly if it is acute. Arterial hypoxaemia arises when venous blood from the tissues, finallymixing in the right side of the heart (mixed venous blood), is not normally oxygenated by passage through thelungs to the left side of the heart and thence the systemic arteries. Direct shunting of blood from the right to theleft side of the heart, bypassing the lungs (as in this case), or perfusion of abnormal shunt vessels in the lungswhich have no contact with alveolar gas are the "shunt" causes of cyanosis. The more common cause, however, isan imbalance or mismatch between ventilation and blood flow among the gas exchanging units of the lung(ventilation-perfusion inequality) which occurs to some degree in most diseases affecting the lungs.

The detection of central cyanosis means that in systemic arterial blood the partial pressure of oxygen (PaO 2 inmmHg), the percentage saturation of haemoglobin (SaO 2 in % oxyhaemoglobin / total haemoglobin), and thecontent of oxygen (CaO 2 in ml/dL of blood) are lower than normal. Useful normal values to remember for a youngadult breathing air at sea level are PaO 2 97 mmHg, SaO 2 97% and CaO 2 20.4 ml/dL, the latter given a normal(total) haemoglobin concentration of 150 gm/L. There is a complex sigmoid relation between PaO 2 as theindependent variable and SaO 2 or CaO 2 as the dependent variable known as the oxyhaemoglobin dissociationcurve. The most important features of this curve are that PaO 2 must fall to 60 mmHg before SaO 2 falls below90% but, thereafter, SaO 2 falls quite steeply such that a PaO 2 of 40 mmHg corresponds with an SaO 2 of 75%.Central cyanosis cannot usually be detected until there is a concentration of 50 gm/L of deoxyhaemoglobin in thearterial blood. It can be seen, from the above relations, that a patient with a normal total haemoglobinconcentration of 150 gm/L would need the SaO 2 to fall to 67% (PaO 2 35 mmHg) before cyanosis could bedetected and this is a very dangerous level of hypoxaemia below the normal mixed venous PO 2 of 40 mmHg.Cyanosis may be detected at a less extreme degree of hypoxaemia when the patient has a high haemoglobin.Detection of cyanosis in the mildly anaemic subject corresponds with a desperately low PaO 2 .

The importance of early detection of hypoxaemia lies in the fact that the body has very small stores of oxygenand most tissues are critically reliant on a continuous adequate arterial content especially the brain and the heart.The oxygen partial pressure (PO ) in the capillary is the immediately critical factor, as oxygen moves along a


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90% but, thereafter, SaO 2 falls quite steeply such that a PaO 2 of 40 mmHg corresponds with an SaO 2 of 75%.Central cyanosis cannot usually be detected until there is a concentration of 50 gm/L of deoxyhaemoglobin in thearterial blood. It can be seen, from the above relations, that a patient with a normal total haemoglobinconcentration of 150 gm/L would need the SaO 2 to fall to 67% (PaO 2 35 mmHg) before cyanosis could bedetected and this is a very dangerous level of hypoxaemia below the normal mixed venous PO 2 of 40 mmHg.Cyanosis may be detected at a less extreme degree of hypoxaemia when the patient has a high haemoglobin.Detection of cyanosis in the mildly anaemic subject corresponds with a desperately low PaO 2 .

The importance of early detection of hypoxaemia lies in the fact that the body has very small stores of oxygenand most tissues are critically reliant on a continuous adequate arterial content especially the brain and the heart.The oxygen partial pressure (PO 2 ) in the capillary is the immediately critical factor, as oxygen moves along apressure gradient to the mitochondria in the cells where the prevailing partial pressure of oxygen is probably lessthan 2 mmHg. However, the oxyhaemoglobin saturation and oxygen content of the arterial blood entering thecapillaries are crucial in maintaining an adequate driving pressure as the oxygen is consumed. For example, theanaemic patient with normal lungs may have a normal PaO 2 and SaO 2 but the low CaO 2 means that the PO 2(and saturation) fall much more rapidly as oxygen is taken up from the capillaries. The precise relation betweenoxygen content and pressure in determining oxygen delivery is incompletely understood.

The important principle is that the causes of hypoxaemia should be rapidly identified and corrected, particularlywhen it is acute. Compensatory mechanisms play an important role in minimising the deleterious effects ofchronic hypoxaemia. The patient in this case is likely to develop these mechanisms including a high cardiac outputand a high total haemoglobin concentration, but these compensations bring other complications.

References



West JB. Respiratory physiology : the essentials. 8th ed. Philadelphia: Wolters Kluwer Health/Lippincott Williams &Wilkins; 2008

West JB. Pulmonary pathophysiology : the essentials. 7th ed. Philadelphia: Lippincott Williams & Wilkins; 2008

West, J. B., 1990, Ventilation/blood flow and gas exchange, 5th ed., Blackwell Scientific

Fauci AS. Harrison's principles of internal medicine. 17th ed. New York: McGraw-Hill Medical; 2008. [ Available asan E-Book] Chapter 35 (Hypoxia and Cyanosis)

Shapiro BA, Harrison RA, Cane RD, Templin R. Clinical Application of Blood Gases. (4th ed.) Chicago: Year BookMedical Publishers, 1989.

Author: Clinical Professor Iven Young, Medicine

LEARNING TOPIC - Detecting alcohol abuse

Alcohol problems can present to a medical practitioner in a multitude of ways. One in six adults presenting togeneral practitioners will be drinking in a hazardous or harmful manner. It has been shown that most of theseproblems or potential problems are undetected and unknown to the doctor. This learning topic addresses thisarea, so students will be familiar with current methods of detection of alcohol related illness.

Medical Presentations of Alcohol Related ProblemsMedical practitioners need to have a high index of suspicion regarding the possibility of alcohol related conditionsand be aware of the presentations where alcohol is likely to be a causative or contributory factor. Teaching needsto emphasize the spectrum of possible presentations of alcohol problems.

• Possible Early Problems o accidents o injuries o trauma o depression, anxiety o psychological problems o social, relationship, family problems o employment difficulties, legal problems o hypertension o arrhythmias o dyspepsia o minor gastrointestinal problems


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• Possible Early Problems o accidents o injuries o trauma o depression, anxiety o psychological problems o social, relationship, family problems o employment difficulties, legal problems o hypertension o arrhythmias o dyspepsia o minor gastrointestinal problems

• Later Stage Problems - In addition to the above - o major gastrointestinal disease - cirrhosis, pancreatitis o neurological disease - alcohol related brain damage, peripheral neuropathy o major cardiovascular disease - cardiomyopathy o dependence and withdrawal

HistoryConsumption, alcohol related problems, features of dependence. Approach to interviewing with regard to possiblealcohol problems, motivational interviewing.

Examination FindingsPhysical signs of possible early alcohol problems, and signs of later problems

Assessment of an alcohol problemHazardous drinking, harmful drinking, alcohol related problems, alcohol dependence

Pathology Tests and Biochemical MarkersGamma Glutamyl Transpeptidase (GGT), Mean Red Cell Volume,

Questionnaires as Screening Instruments

References



Latt, N., Conigrave, K., Saunders, J., Nutt, D., (eds), 2009, Addiction Medicine. OUPHulse, G., White, J., Cape, G., (eds.), 2002, Management of alcohol and drug problems, OUP, SouthMelbourne.Optional references:

Audit Questionnaire. See Learning topic: Early intervention for harmful drinking Problem 2.03 Newwheels

Australian Alcohol Guidelineswww.nhmrc.gov.au/publications/synopses/_files/ds10-alcohol.pdf

Author: Dr Ken Curry, Addiction Medicine

LEARNING TOPIC - Discovery of circulation: Harvey film (TIMETABLE)


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Author: Dr Ken Curry, Addiction Medicine

LEARNING TOPIC - Discovery of circulation: Harvey film (TIMETABLE)

William Harvey is regarded as the originator of modern medical science, and the video will show howhe came to his revolutionary conclusion that the blood flows in a continuous circle around the body.Like Copernicus he made his great discovery without recourse to novel scientific instruments, butstimulated by the intellectual freedom of the Renaissance he encountered during his student years inPadua.

Although Harvey broke out of the belief in tidal flow of blood through (non-existant) holes in theinterventricular septum which had endured unchallenged from ancient times, he remained politicallyconservative and retained many of the other scientific ideas developed by Aristotle and Galen. Forinstance he not only dedicated his book to King Charles I, but in his preface compared the monarchyand its role in society to the heart which was the source of the "innate heat" which distinguished theliving from the dead.

That is, Harvey looked both forwards and backwards as we all still do. New discoveries and conceptsare assimilated into the paradigms passed on from our predecessors and in the process must berelated to our view of the world. Lag in this process of incorporation of new medical ideas into theculture of a society affects the relationship between patients and doctors and is important in shapinggoverment health policies

Please see timetable for time and location of film

References



University of Sydney. Dept. of Infectious Diseases. 1990, 'The Four Elements and the four humours' inHistory and philosophy of medicine for medical students , The Department, Sydney, N.S.W.

Aubrey, J., 1999, "William Harvey" in Aubrey's Brief lives. O. L. Dick (ed.) Boston, Mass.


LEARNING TOPIC - Doctors' dilemmas: treating friends family

Treating family and friends.

There is a long-standing prejudice against treating family and friends, because the relationshipbetween the carer and the ill person is too close. It is not illegal, but it is discouraged. Why should itmatter? It might even be argued that the closeness and understanding should lead to bettermanagement, rather than to problems. To understand why there is a very real problem, we need toexamine why people consult doctors, how patients and doctors conduct their transactions and howthe relationship of family or friend may interfere with these transactions.

Why do people consult doctors ?

People ask for medical help for more reasons than might seem obvious. The reasons can beconveniently considered under seven headings. Most obviously, they have developed symptomsand/or signs which obviously threaten their autonomy and quality or duration of life (abdominal pain,swollen joints, sore throat, depression, for example). Others have a symptom/sign complex whichdoes not cause any obvious ill health, but threatens to do so in the future (symptomless breast lump,symptomless hypertension). A third group have no evidence of disease, but have reason to fear thatthey will develop a more or less serious illness (family history of colon cancer, hepatitis B exposure,relationship with HIV sufferer). A fourth group will be in good health and wants to stay that way byensuring health screening and health advice (health maintenance plan, breast screening). A fifth willhave developed patterns of coping with life which involve using illness as a shelter (abnormal illnessbehaviour, some chronic pain syndromes). A sixth will not perceive that they are ill, but are sent by


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People ask for medical help for more reasons than might seem obvious. The reasons can beconveniently considered under seven headings. Most obviously, they have developed symptomsand/or signs which obviously threaten their autonomy and quality or duration of life (abdominal pain,swollen joints, sore throat, depression, for example). Others have a symptom/sign complex whichdoes not cause any obvious ill health, but threatens to do so in the future (symptomless breast lump,symptomless hypertension). A third group have no evidence of disease, but have reason to fear thatthey will develop a more or less serious illness (family history of colon cancer, hepatitis B exposure,relationship with HIV sufferer). A fourth group will be in good health and wants to stay that way byensuring health screening and health advice (health maintenance plan, breast screening). A fifth willhave developed patterns of coping with life which involve using illness as a shelter (abnormal illnessbehaviour, some chronic pain syndromes). A sixth will not perceive that they are ill, but are sent byfamily or friends who do perceive a change (occult cerebral tumour, alcoholism). Finally, a seventhgroup present because they find themselves overwhelmed by anxiety or other symptoms of angst(anxiety states, grieving, burnout).

The nature of the clinical transaction

Doctor and patient work within an agency relationship, in which the patient entrusts the doctor tobecome his/her agent in order to secure something which s/he desires. All such relationships arebased on trust. Doctor and patient use language and signs to communicate and elucidate the problemof the illness. The doctor translates the patient's account into his/her own language, and then back tothe patient's language when s/he comes to explain what is wrong and what should be done. By theuse of language and signs, doctor and patient should ideally achieve an intersubjective relationship,whereby the doctor understands the nature of the illness and how it affects this particular individual.Within this relationship, doctor and patient decide together what the right action may be. Thetransaction begins with the power markedly unbalanced in favour of the doctor and should end with arestoration of power to the patient.

The problems of treating family and friends.

Family and friends do not stand in an agency relationship with you as a doctor. They may trust you,but may also find it difficult to accept your authority when you give advice. It is likely that they willappeal to your special relationship and to make special judgements which may not accord with yourown perceptions of right action. The language you commonly use with family and friends is not thelanguage of medicine, and linguistic communication is easily distorted. It is particularly hard to offerprobabilistic advice to family and friends who want to know what will happen to them as uniqueindividuals. It is also hard to break bad news without offering false hopes. This all occurs becauseintersubjectivity is replaced by sympathy and identification with the other. You are connected withthe other by special social and emotional bonds.

References



Little, J. M., 1995, Humane medicine., Cambridge University Press, Cambridge, U.K. pp. 15-29,61-73,141-159.

Broyard, A., 1992, Intoxicated by my illness : and other writings on life and death, FawcettColumbine, New York

Ingelfinger F. Arrogance. New Engl J Med 1980; 303(26): 1507-1511.

Rabin D. Occasional notes: Compounding the ordeal of ALS: isolation from my fellow physicians. NewEngl J Med 1982; 307(8): 506-509.

Author: Dr Narelle Shadbolt, General Practice

LEARNING TOPIC - Drug therapy for stable effort angina

It is important to understand the mechanism of symptoms in order to treat angina. Effort relatedangina pectoris is the symptom produced by myocardial ischemia. Effort angina results from 'demandischemia' -- an increase in myocardial oxygen demand in excess of the ability of the coronarycirculation to increase blood flow and supply oxygen.

The major determinants of myocardial oxygen demand are

heart ratewall stress: the product of left ventricular diastolic dimension and afterload (systolic bloodpressure and arterial distensibility)


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It is important to understand the mechanism of symptoms in order to treat angina. Effort relatedangina pectoris is the symptom produced by myocardial ischemia. Effort angina results from 'demandischemia' -- an increase in myocardial oxygen demand in excess of the ability of the coronarycirculation to increase blood flow and supply oxygen.

The major determinants of myocardial oxygen demand are

heart ratewall stress: the product of left ventricular diastolic dimension and afterload (systolic bloodpressure and arterial distensibility)myocardial contractility

All of these increase with physical effort, and emotion or sexual intercourse, and provoke demandischemia which may result in angina.

The main reason for limitation of coronary blood flow is atherosclerotic obstruction to the epicardialcoronary arteries of > 50% lumen diameter reduction. Microvascular abnormalities secondary toendothelial dysfunction may also limit vasodilator reserve. Because coronary blood flow occurs mostlyin diastole, and because tachycardia reduces diastolic time, tachycardia itself may limit coronaryblood flow.

Both the doctor and the patient should understand that angina is merely a symptom of ischemia sodrug therapy should not aim to merely relieve pain but must reduce ischemia. This can beaccomplished by reducing the myocardial oxygen demand through blockade of the heart rate increasewith exercise, and reduction in afterload and ventricular volume with a vasodilator. Exercise trainingmay have a similar effect. The other approach to management of angina is the obstruction to coronaryblood flow with bypass surgery or percutaneous coronary intervention (balloon angioplasty usuallywith stenting).

Treatment of angina using antianginal drugs may relieve symptoms but will not necessarily improveprognosis. Almost 1 in 3 patients in primary care with stable angina have weekly angina, and thisimpairs quality of life, making it important for us to assess this and appropriately manage angina.Because patients with coronary disease have an increased risk of death and myocardial infarction,drugs which can reduce this risk should be given. These include aspirin, the statins, angiotensin-converting enzyme inhibitors and probably fishoils. Lifestyle measures such as exercise, exercisetraining, diet and smoking cessation should also be advised. These measures may reduce angina inaddition to improving the prognosis.

Antianginal drugs

Nitrates. These drugs relax vascular smooth-muscle through a cyclic GMP mechanism and areboth arterial and venodilators. Afterload and ventricular dimension are both reduced, andcollateral blood flow increased. The short acting nitrates such as nitroglycerin sublingual tabletsor spray, or isosorbide dinitrate sublingual tablets can be taken in the mouth (not swallowed)immediately angina is experienced. They are also very effective if taken prophylactically justbefore angina. NB limited shelf-life, and instability of nitroglycerin tablets if removed from theoriginal glass container. The long acting nitrates including sustained release preparations ofisosorbide mononitrate and isosorbide dinitrate and nitroglycerin transcutaneous preparations,can be used to provide a more sustained effect than the short acting preparations. Unfortunatelylong acting nitrates will produce tolerance within 24 hours unless a nitrate-free or nitrate-poorperiod of approximately 10 hours (often overnight) is provided in the regimen.The main sideeffect of nitrates is headache due to vasodilatation. Nicorandil is a novel nitrate with anadditional potassium channel opening effect and may have a beneficial effect on prognosis.

1.

Beta-blockers. These drugs reduce the heart rate and blood pressure at rest and during exerciseand are very effective in patients with angina. They may also improve prognosis, but probablyonly if there is left ventricular dysfunction. The drugs most used are the beta-1 selectiveblockers (atenolol , metoprolol and bisoprolol) which have a lesser tendency to aggravateasthma or peripheral vascular disease than the non-selective beta-blockers. Metoprolol has alarge first-pass metabolism and the drug dose must be titrated to achieve the desired heart rateresponse. The beta-blockers may also cause unwanted effects such as fatigue, loss of libido andimpotence, and bad dreams.

2.

Calcium entry blockers. These drugs are arterial dilators and reduce blood pressure andafterload. Verapamil and diltiazem also have some heart rate slowing and myocardial depressanteffects which may be useful in treatment of angina. The long acting dihydropyridine drugsnifedipine (only in a sustained release formulation) and amlodipine are more potent vasodilatorswith minimal heart rate and myocardial effects. All drugs in this class can produce vasodilatorside effects such as flushing, hypotension, and edema. They can be combined with beta-blockersalthough combinations may produce adverse effects including hypotension (all) andbrachycardia, heart block and heart failure (verapanil and dilatiazem). These drugs should not

3.


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response. The beta-blockers may also cause unwanted effects such as fatigue, loss of libido andimpotence, and bad dreams.

Calcium entry blockers. These drugs are arterial dilators and reduce blood pressure andafterload. Verapamil and diltiazem also have some heart rate slowing and myocardial depressanteffects which may be useful in treatment of angina. The long acting dihydropyridine drugsnifedipine (only in a sustained release formulation) and amlodipine are more potent vasodilatorswith minimal heart rate and myocardial effects. All drugs in this class can produce vasodilatorside effects such as flushing, hypotension, and edema. They can be combined with beta-blockersalthough combinations may produce adverse effects including hypotension (all) andbrachycardia, heart block and heart failure (verapanil and dilatiazem). These drugs should notbe used in patients with stable angina who also have heart failure.

3.

Perhexiline. This is a carnitine palmityl transferase-2 inhibitor which reduces the myocardialrequirement for aerobic metabolism. The drug is very useful in refractory cases but blood levelsmust be monitored closely because a significant proportion of the population are geneticallydetermined very slow drug metabolisers and will achieve very high blood levels which are bothhepatotoxic and neurotoxic. Another metabolic agent not available in Australia is Ranolazine.

4.

Ivabradine. This is a novel drug that blocks the If channel in the sinus node, and slows the heartrate at rest and during exercise. It therefore has a similar action to the beta-blockers, butwithout beta adrenoreceptor blockade. The only side effect (uncommon) is phosphenes, a yellowcoloration of vision which is reversible.

5.

Angiogenic drugs, genes, stem cells. A number of angiogenic cytokines, genes and stem cells arecurrently under investigation in patients with end-stage coronary artery disease. The hope isthat angiogenesis will be induced to provide new collateral vessels and an increase in coronaryblood flow without the need for revascularisation.

6.

Intractable angina. Patients with angina refactory to drug therapy, lifestyle measures, and arewho unsuitable for revascularization, may benefit from a period of external counterpulsation(pumps applied to limbs and torso timed to inflate or deflate according to the cardiac cycle).Other alternatives include spinal chord stimulation, TENS, and cervical sympathectomy.

7.

References


See relevant sections of:

Rang, H. P. and M. M. Dale, 2007, Rang and Dale's Pharmacology, 6th ed., Churchill Livingstone,Edinburgh

Boon, N. A. and S. Davidson, 2006, Davidson's principles & practice of medicine, 20th ed.,Elsevier/Churchill Livingstone, Edinburgh ; New York

Author: Professor Ben Freedman, Medicine

LEARNING TOPIC - Essential Life Support

Learning Topic: Essential Life Support Dr Michele Franks MBBS, FACEM. Northern Clinical School, USydDiscipline of Emergency Medicine Essential life support is the maintenance of airway, breathing and circulation in the person who hassuddenly become extremely unwell or severely injured. Objectives for the BLS topic are to: 1. Effectively care for a patient that suddenly becomes unconscious or very unwell in the

community setting;2. Demonstrate appropriate airway opening manoeuvres, jaw thrust / head tilt / chin lift;3. Demonstrate correct mouth to mouth / mask and bag-valve –mask ventilation;4. Demonstrate effective external chest compression;


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Essential life support is the maintenance of airway, breathing and circulation in the person who hassuddenly become extremely unwell or severely injured. Objectives for the BLS topic are to: 1. Effectively care for a patient that suddenly becomes unconscious or very unwell in the

community setting;2. Demonstrate appropriate airway opening manoeuvres, jaw thrust / head tilt / chin lift;3. Demonstrate correct mouth to mouth / mask and bag-valve –mask ventilation;4. Demonstrate effective external chest compression;5. Explain safety precautions associated with using defibrillation;6. Demonstrate operation of an AED (automatic external defibrillator);7. Demonstrate management of unconscious person including positioning;8. Identify complications that may arise during BLS In general, the clinical signs of critical illness are similar whatever the underlying process, becausethey reflect failing respiratory, cardiovascular and neurological systems. The initial approach to thecollapsed patient is always the same using the algorithm DRABC.

D - Danger… Is the area safe? Are there electrical cables, broken glass, traffic? Is the patient inwater, on unstable ground? Remove patient from danger while maintaining your own safety.

R - Response…Talk to the patient. No response?... then try to awaken the person by tappingyour hand on their shoulder, then calling their name. Call for help – 112 on mobile, 000 onlandline… yell out to other bystanders.

A - Airway… Look in the mouth; remove any foreign object (eg food). Open the airway, headtilt/chin lift. Jaw thrust if cervical spine injury suspected.

B - Breathing… Look, listen and feel. If no breathing or inadequate breathing, ventilate usingexpired air resuscitation, mouth to mask or bag-valve –mask ventilation, attach supplementaloxygen if available. Give 2 breaths.

C - Circulation…Check carotid pulse or if no signs of life, start chest compressions – ratio 30compressions to 2 breaths, at a compression rate of 100/minute. Attach AED as soon asavailable and follow prompts. Continue CPR until help arrives, patient shows signs of life or youcan no longer sustain resuscitative efforts. AEDs are designed to be used by untrained orminimally trained personnel. AEDs are usually found in crowded areas such as airports, sportingstadiums, etc. If person starts to breath and has a pulse they can be put into the recoveryposition.

Author: Dr Michele Franks, Medicine

LEARNING TOPIC - Features of Down syndrome

Down syndrome is diagnosed where there is effectively trisomy for chromosome 21 (see learningtopic on Chromosomal abnormalities and early development in Down syndrome).

The features which Dr Langdon Down identified in 1866 as 'mongoloid' are present in many but not allpatients with Down syndrome. The dysmorphic, i.e. abnormal craniofacial features, are modified byfamilial and ethnic facial features. Down syndrome may be found in children and adults in everyethnic group throughout the world. The dysmorphic features which are identified with Downsyndrome may be found in a large number of other syndromes. Thus the presence of the featuressingly or in combination is never diagnostic, but a suspicion of Down syndrome should always beconfirmed by chromosomal study.

Features which are commonly seen in the Newborn with Down syndrome:


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Down syndrome is diagnosed where there is effectively trisomy for chromosome 21 (see learningtopic on Chromosomal abnormalities and early development in Down syndrome).

The features which Dr Langdon Down identified in 1866 as 'mongoloid' are present in many but not allpatients with Down syndrome. The dysmorphic, i.e. abnormal craniofacial features, are modified byfamilial and ethnic facial features. Down syndrome may be found in children and adults in everyethnic group throughout the world. The dysmorphic features which are identified with Downsyndrome may be found in a large number of other syndromes. Thus the presence of the featuressingly or in combination is never diagnostic, but a suspicion of Down syndrome should always beconfirmed by chromosomal study.

Features which are commonly seen in the Newborn with Down syndrome:

HypotoniaExcessive skin folds at the back of the neckMaxillary (malar) underdevelopment (hypoplasia)In curving of the little finger (clinodactyly)Hypoplasia of the middle phalanx of the 5th finger - recognised by a short middle segment or asingle interphalangeal crease.Wide gap between the first or second toes (sandal gap)

Features which may be seen in normal newborns

Epicanthic folds (prominent skin folds at the inner canthi of the eyes) which are usually seen in babiesof African and Asian descent and not uncommonly in European infants.

Single transverse palmar crease

Down syndromeNormal

Bilateral 45% 1%

Unilateral 4%

Major malformations in the Newborn with Down syndrome

Congenital Heart Anomalies (40%)Atrio-ventricular canal (13%)Ventricular septal defects (13%)Tetralogy of Fallot (7%)Atrial septal defects (10%)Gastrointestinal Anomalies (10-18%)Duodenal atresiaHirschsprung diseaseUndescended testes (21%)

Features commonly seen in childhood

Delayed psychomotor developmentIntellectual disabilityProminence of the tongue (due to a small mouth)Persistent epicanthic foldsFlattening of the back of the head (brachycephaly)Short statureBrushfield spots (speckling around the rim of the iris) except in subjects with brown iridesJoint hypermobility

Preventive health maintenance in childhood

Leukoerythroblastic anaemiaAcute LeukaemiaHypothyroidismAtlanto-Occipital Instability

Preventive health maintenance in adults



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Preventive health maintenance in adults


Specific terminologic notes

By international convention the term 'mongolism' had been abandonedSyndromes are named without the possessive ie Down syndrome, Edwards syndrome etc.'Simian' means 'pertaining to a monkey'. It is an inappropriate (obsolete) term for 'singletransverse palmar crease' or 'bridged transverse palmar crease' which should be distinguishedfrom the Sydney line which is a proximal complete transverse palmar crease in the presence of apartial distal palmar crease.

References



Chromosomal syndromes : common and/or well-known syndromes in 2001, Syndromes of the headand neck, Oxford Monographs on Medical Genetics NO. 42, ed. R. J. Gorlin, et al. New York, OxfordUniversity Press: Pages 35-42.

Gardner, R. J. M. and G. R. Sutherland, 2004, Chromosome abnormalities and genetic counseling, 3rded., Oxford University Press, New York. Pages 249-263

Selikowitz, M., 1997, Down syndrome : the facts, 2nd ed., Oxford University Press, Oxford ; New York,204 pp.

Antonarakis S, Lyle R, Dermitzakes ET, Reymond A, Deutsch S. Chromosome 21 and Down Syndrome:from genomics to pathophysiology. Nature Reviews Genetics 2004; 5(10): 725-737.

There is extensive literature on the molecular mechanisms resulting in Down syndrome. This reviewgives an extensive coverage of the information on the correlation between molecular mechanisms andphenotype.


LEARNING TOPIC - Flow and pressures in the circulation

The flow of blood around the body is driven by pressure, generated by the pump action of the heart'sventricles. Within the circulation, the arteries contain blood under high pressure but there is a markedreduction in pressure within the microcirculation and capillaries. The veins are a low pressure systemfor return of blood to the heart. The pulmonary circulation normally operates at a lower pressure thanthe systemic circulation.

The cardiac cycle consists of two major phases: diastole, when the ventricles are being filled withblood and systole when the ventricles contract to eject blood from the heart. In diastole the ventriclesare relaxed and fill from the atria with blood flowing across the open atrio-ventricular valves. Thewalls of the ventricle are distended as it fills. With the onset of systole, an electrical impulse causesthe walls of the ventricle to begin contracting. As the ventricle contracts, the pressure within thechamber rises and forces the atrio-ventricular valve shut. The ventricle continues to contract(isovolumic contraction period) and pressure within the chamber rises further before forcing thesemi-lunar valve open and ejecting blood into the aorta (or pulmonary artery). The blood ejected fromthe ventricle is the stroke volume. At the end of this ejection period, pressure within the ventriclebegins to fall as the muscle relaxes. The semilunar valve closes and ventricular chamber pressure fallsfurther (isovolumic relaxation). During this time the atria have been collecting blood from the veins,ready for the next beat. When ventricular pressure falls below the atrial pressure, the atrio-ventricular valve opens and blood flows from the atrium to the ventricle to begin the next cycle.Mechanical systole is the period from onset of rise of ventricular pressure to the closure of thesemi-lunar valve.


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chamber rises and forces the atrio-ventricular valve shut. The ventricle continues to contract(isovolumic contraction period) and pressure within the chamber rises further before forcing thesemi-lunar valve open and ejecting blood into the aorta (or pulmonary artery). The blood ejected fromthe ventricle is the stroke volume. At the end of this ejection period, pressure within the ventriclebegins to fall as the muscle relaxes. The semilunar valve closes and ventricular chamber pressure fallsfurther (isovolumic relaxation). During this time the atria have been collecting blood from the veins,ready for the next beat. When ventricular pressure falls below the atrial pressure, the atrio-ventricular valve opens and blood flows from the atrium to the ventricle to begin the next cycle.Mechanical systole is the period from onset of rise of ventricular pressure to the closure of thesemi-lunar valve.

In adults, the normal end-diastolic left ventricular volume is approximately 70 ± 20 ml/m 2 s and the

normal residual volume in the ventricle at end-systole is 25 ± 10 ml/m 2 s. The ejection fraction is theproportion of the end-diastolic volume which is ejected during each systole and is typically 50-70%for the left ventricle. The cardiac output is the amount of blood pumped from the heart each minuteand is the stroke volume per beat multiplied by the heart rate.

The flow of blood between heart chambers is dependent upon the pressures within each chamber. Theatria are low pressure chambers with mean right atrial pressure being 3-5 mmHg and mean left atrialpressure being 5-10 mmHg. In diastole the ventricles have low chamber pressures, being 1-3 mmHgat the onset of ventricular filling. During diastole, ventricular filling pressure increases to 5-7 mmHgin the right ventricle and 8-10 mmHg in the left ventricle by end-diastole. During systole there is amarked increase in ventricular chamber pressures to approximately 20-25 mmHg in the right ventricleand 110-130 mmHg in the left ventricle. Normal pulmonary artery pressures are approximately 25/12mmHg and normal aortic pressures are approximately 120/80 mmHg, because the systemic arterialvascular resistance is higher than the pulmonary vascular resistance.

References



Boon, N. A. and S. Davidson, 2006, Davidson's principles & practice of medicine, 20th ed.,Elsevier/Churchill Livingstone, Edinburgh ; New York.



LEARNING TOPIC - Functions of the heart as a pump

Structure of the Myocardium

Understand the macroscopic structure of the myocardium as a syncytium of myocytes containingcontractile myofilaments. Myofilaments contain both contractile proteins (actin and myosin) andregulatory proteins (such as troponin and tropomyosin). These proteins are assembled intosarcomeres, which are the contractile units of the myocardium. The structure of the sarcomeres ismaintained by additional proteins, such as titin. Refresh your knowledge of the structure of the actinand myosin molecules and how they are believed to interact to generate contractile force. Theinteraction of the myosin head with an exposed actin binding site is central to the contractile process.After binding to actin and myosin, the myosin molecule bends at the head-rod junction and thisprotein deformation shortens the myofilament (power stroke). Repetition of the power strokeshortens the muscle. This process requires hydrolysis of ATP at the rate of 1 ATP molecule per powerstroke per myosin molecule. Understand the role of regulatory proteins, including tropomyosin andTroponin-T in the actin-myosin interaction.

Pump action of the heart

The heart functions as a pump in systole to eject blood into the circulation. During diastole, theventricle fills with blood from the atrium. At end-diastole, the mitral valve closes and ventricularpressure rises. The aortic valve opens and blood is ejected into the circulation. At end-systole, theventricle begins to relax, ventricular pressure falls and the aortic valve closes and then the mitralvalve opens to begin the next cardiac cycle. The volume of blood ejected from the ventricle is thestroke volume and the cardiac output is the product of stroke volume and heart rate. The work doneby the heart in each beat is the integral product of the stroke volume and ventricular pressuregenerated during systole.

The degree to which a sarcomere shortens is dependent upon its initial load (preload) and the loadagainst which it must contract (afterload). In the heart, an increase in venous return to the ventricle


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The heart functions as a pump in systole to eject blood into the circulation. During diastole, theventricle fills with blood from the atrium. At end-diastole, the mitral valve closes and ventricularpressure rises. The aortic valve opens and blood is ejected into the circulation. At end-systole, theventricle begins to relax, ventricular pressure falls and the aortic valve closes and then the mitralvalve opens to begin the next cardiac cycle. The volume of blood ejected from the ventricle is thestroke volume and the cardiac output is the product of stroke volume and heart rate. The work doneby the heart in each beat is the integral product of the stroke volume and ventricular pressuregenerated during systole.

The degree to which a sarcomere shortens is dependent upon its initial load (preload) and the loadagainst which it must contract (afterload). In the heart, an increase in venous return to the ventriclewill cause it to stretch the sarcomere during diastole. As a result the sarcomere will shorten more inthe next systole. This is the Frank-Starling principle and it is an important physiological modulator ofthe force of cardiac contraction. In patients with heart disease, who have a reduced contractilefunction of the heart, the Frank-Starling mechanism is used to partly restore contractile function. TheFrank-Starling mechanism does not usually fully compensate for depressed cardiac function inpatients with heart failure and it is not possible to stretch sarcomere indefinitely. If the sarcomere isoverstretched, contractile force declines. If diastolic pressure in the left ventricle becomes too high,then the patient will suffer pulmonary congestion.

The degree of afterload on the ventricle is important. Afterload is a multifactorial identity, influencedby arterial pressure, aortic valve function and arterial impedance. An increase in afterload will resultin a reduction of the degree of shortening of the sarcomere and a reduction in stroke volume andcardiac output.

References





LEARNING TOPIC - Genesis of atheroma

Atherosclerosis involves cellular proliferation, inflammation, intracellular and extracellular depositionof lipoprotein-derived lipid (principally cholesterol and cholesteryl ester), deposition of extracellularmatrix, and, of particular importance in the clinical management of ischaemic heart disease,thrombotic occlusion of coronary vessels. Diabetes, hypercholesterolaemia, smoking, hypertension,male sex, increasing age, positive family history, sedentary lifestyle and obesity are all establishedrisk factors for coronary atherosclerosis.

Native or modified (oxidised, glycosylated or aggregated) low density lipoprotein (LDL) in the arterialintima may induce monocyte infiltration to initiate atherosclerosis. Arterial branch points arepredisposed to atherosclerosis. This appears due to increased turbulence, cell turnover andpermeability of endothelium at branch points.

Endothelium is normally non-thrombogenic and non-adherent for leukocytes. The expression ofadhesion molecules by endothelial cells is critical for the initial reversible rolling and subsequentirreversible firm adhesion and diapedesis by monocytes. Cytokines augment leukocyte-endothelial celladhesion by promoting the expression of endothelial adhesion molecules (eg VCAM-1) and monocyteligand molecules (eg integrins). The endothelium maintains vascular tone by releasing prostacyclin(PGI2, dilator), endothelin (ET, constrictor) and endothelium-derived relaxing factor (EDRF, whichmay be at least in part nitric oxide, NO). Impaired endothelial cell-mediated dilatation is an earlyfeature of atherosclerosis.

Fatty streaks arise from the endothelial penetration of blood-borne monocytes which subsequentlybecome 'foam-cell' macrophages laden with lipid. Plaque progression leads to the development of thefibrofatty lesion, which is frequently eccentric and can result in significant luminal stenosis. Itbecomes increasingly 'fibrous' and 'complex' with a dense cap of connective tissue and smoothmuscle cells (SMC) overlying a core of lipid and necrotic cells (necrotic core). Matrix and connectivetissue are deposited by SMC, many of which are also 'foam-cells' . Cell proportions in lesions vary,with more SMC in coronaries and more macrophages in aortae.

Immunologically active T-lymphocytes, mast cells, immunoglobulins, terminal C5b-9 complementcomplex and complement receptors are present in atheroma. Complement activation may follow thedeposition of antibodies to antigens such as native, glycosylated or oxidised lipoproteins, infectious


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Fatty streaks arise from the endothelial penetration of blood-borne monocytes which subsequentlybecome 'foam-cell' macrophages laden with lipid. Plaque progression leads to the development of thefibrofatty lesion, which is frequently eccentric and can result in significant luminal stenosis. Itbecomes increasingly 'fibrous' and 'complex' with a dense cap of connective tissue and smoothmuscle cells (SMC) overlying a core of lipid and necrotic cells (necrotic core). Matrix and connectivetissue are deposited by SMC, many of which are also 'foam-cells' . Cell proportions in lesions vary,with more SMC in coronaries and more macrophages in aortae.

Immunologically active T-lymphocytes, mast cells, immunoglobulins, terminal C5b-9 complementcomplex and complement receptors are present in atheroma. Complement activation may follow thedeposition of antibodies to antigens such as native, glycosylated or oxidised lipoproteins, infectiousagents, or could represent a direct activation of complement by extracellular lipids such as thosepresent in the necrotic core of atherosclerotic plaque.

Contractile and synthetic SMC phenotypes have been described in plaque. Growth factors such asplatelet derived growth factor (PDGF) can induce the change from contractile to synthetic phenotypeand the subsequent release of cytokines, growth factors, and extracellular matrix from synthetic SMC.Conversely, components of extracellular matrix (eg heparan sulphate) can inhibit SMC transformation,proliferation and migration.

Further rapid progression of atherosclerosis leads to plaque instability. Fissuring of an advancedfibrofatty plaque may develop as a result of collagen rupture. Endothelial cell separation anddenudation permits platelet adhesion to exposed subendothelium and foam cell macrophages withsubsequent development of intraluminal thrombosis. Mild plaque fissuring causing intraplaquehaemorrhage can cause significantly increased coronary stenosis without necessarily causing luminalthrombosis and occlusion, while deep fissuring is more likely to be associated with vessel occlusion bythrombosis. A deep fissure is also likely to permit escape of some of the necrotic core as anatheroembolus which will travel 'downstream' and may occlude distal arterial branches. Duringorganisation of thrombus, growth factors from adherent platelets promote SMC proliferation.

Regression of atherosclerotic lesions in non-human primates occurs more readily in fatty streaks thanin raised fibrous lesions and is associated with an increase in lesion calcification and collagendeposition and a decrease in lesion cholesteryl ester content. However, arteries do not return to theirprediseased state. Thus lowering serum cholesterol may preferentially induce regression offoam-cell-rich fatty streaks and perhaps reduce the cellularity and lipid content of macrophage- andlipid-rich lesions of advanced plaque, but only produce mild changes in the degree of angiographicallyapparent coronary stenosis.

References



Kumar, V., et al., 2005, Robbins and Cotran pathologic basis of disease, 7th ed., Elsevier Saunders,Philadelphia. [Available as a E-Book] Chapter 11 (Blood Vessels > Atherosclerosis)

Provides an illustrated overview of the morphological features of atherosclerosis.

Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s . Nature 1993; 362(6423):801-809.

Fuster V, Badimon L, Badimon JJ, Chesebro JH. The pathogenesis of coronary artery disease and theacute coronary syndromes-part 1. N.Engl.J.Med. 1992; 326(4): 242-250.

Davies MJ, Woolf N. Atherclerosis: what is it and why does it occur? Brit.Heart J. 1993; 69(Suppl.):3-.11.

For extra detail, the following references give overlapping but complementary views of thedevelopment of atherosclerosis. Reference 1 covers cellular interactions and cytokines in some detail,reference 2 outlines the potential role of plaque fissuring in lesion progression, and reference 3outlines the important features of plaque predisposing to plaque rupture and acute coronarysyndromes.

Author: Professor Len Kritharides, Medicine


LEARNING TOPIC - Gross and fine anatomy of blood vessels

Anatomy of the coronary arteries


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syndromes.

Author: Professor Len Kritharides, Medicine


LEARNING TOPIC - Gross and fine anatomy of blood vessels

Anatomy of the coronary arteries

Revise the general structure of the heart from the learning topic Structure of heart and greatvessels . In particular the position of the external sulci.What is the origin, course and main branches of the left and right coronary arteries?Which arteries or branches supply the left and right ventricles, the interventricular septum andthe conducting system?Where do the branches of these two arteries anastomose with each other? What is thesignificance of the anastomosis?

Histology

How does the histological structure of elastic and muscular arteries, arterioles and capillariesvary?

Additional

How is the venous drainage of the heart organised?Which nerves innervate the coronary arteries and what effect do they have on coronary bloodflow?

References

Moore, K. L., et al., 2006, Clinically oriented anatomy, 5th ed., Lippincott Williams & Wilkins,Baltimore, MD. Chapter 3 (Pelvis & Perineum)

Drake, R. L., et al., 2005, Gray's anatomy for students, ed., Elsevier/Churchill Livingstone,Philadelphia. Chapter 3 (Thorax)

Ross, M. H. and W. Pawlina, 2006, Histology : a text and atlas with correlated cell and molecularbiology, 5th ed., Lippincott Wiliams & Wilkins, Baltimore, MD. Chapter 13 (Cardiovascular system)

Author: Dr Richard Ward, Anatomy and Histology

LEARNING TOPIC - History of chronic fatigue syndrome

Chronic Fatigue was first considered a pathological entity in the 1750s.

In the 1800s the syndrome had many different names and there was much debate as to the cause. Itwas variably called nervous exhaustion, weak nerves, neurasthenia, autonomic imbalance syndromeor Da Costa syndrome.

The 20th century has seen this entity linked to many diseases, such as Brucellosis, epidemicneurasthenia, chronic EBV (Epstein-Barr virus) syndrome, total allergy syndrome, and chronic yeastinfection.

The application of scientific techniques has yet to elucidate a definite cause for this constellation ofsymptoms with fatigue as its central symptom.

Chronic fatigue syndrome was in recent history most fully described as Myalgic Encephalomyelitis(ME). This illness was thought to be related to a coxsackie virus infection and first occurred inCoventry and then at the Royal Free Hospital in London in 1955.

Since that description of the syndrome Chronic Fatigue System or ME has been in a state of evolution,and it was in the late 1970s and early 1980s when it reached its peak in the literature. In 1988 theCentre for Disease Control in Atlanta published what has become the working definition for chronicfatigue syndrome.

Debate is still spirited in the literature, with those who believe Chronic Fatigue Syndrome is a physical


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symptoms with fatigue as its central symptom.

Chronic fatigue syndrome was in recent history most fully described as Myalgic Encephalomyelitis(ME). This illness was thought to be related to a coxsackie virus infection and first occurred inCoventry and then at the Royal Free Hospital in London in 1955.

Since that description of the syndrome Chronic Fatigue System or ME has been in a state of evolution,and it was in the late 1970s and early 1980s when it reached its peak in the literature. In 1988 theCentre for Disease Control in Atlanta published what has become the working definition for chronicfatigue syndrome.

Debate is still spirited in the literature, with those who believe Chronic Fatigue Syndrome is a physicalillness and those who believe it is psychological in nature. Most authorities seem to believe that it is acombination of both these factors.

As with any chronic illness with no effective treatment of defined aetiology, there is a chronic fatigueindustry offering many unproven cures to the patients with this illness. There are also many supportgroups keeping patients informed of the progress of research and raising funds for research into thisillness as is shown in some of the Internet references below.

References



Holmes GP, Kaplan JE, Gantz NM et al. Chronic Fatigue syndrome: a working case definition. Ann. Int.Med 1988; 108(3): 387-389

Hickie I, Lloyd A, Wakefield D, Parker G. The psychiatric status of patients with chronic fatiguesyndrome. Br. J. Psychiatry 1990; 156: 534-540

Medical Staff of the Royal Free Hospital. An outbreak of encephalomyelitis in the Royal Free Group,London in 1955. Br Med J 1957, October, 2: 895-904

Internet Sites

(The contents of these sites may not necessarily be based on evidence.)

The American Association for Chronic Fatigue Syndrome (AACFS): http://www.aacfs.org/ .

Chronic Fatigue Syndrome/Myalgic encephalomyelitis Information Page: http://www.cfs-news.org/ .

Author: Dr Ravinay Bhindi, Medicine

LEARNING TOPIC - Immune mechanisms in rheumatic fever

The association of acute pharyngeal infection with beta-haemolytic Group A Streptococci and acuterheumatic fever (ARF) is the most compelling example of an acute bacterial infection inducing tissuedamage through auto-immune mechanisms. Following untreated clinical pharyngitis with a widevariety of streptococcal serotypes, about 3% of subjects will develop ARF involving the joints, skinand the heart. In a minority of patients (10-15%), involvement of the basal ganglia will cause apattern of involuntary movements, termed chorea. Many, but not all, serotypes are capable of leadingto ARF, and high attack rates are associated with virulent strains belonging to several M-proteinserotypes.

Anti-cardiac auto-antibodies and molecular mimicry

Patients with ARF develop antibodies which react with cardiac tissue. This led to the concept of'molecular mimicry', which refers to the sharing of antigenic determinants by the initiating infectiousagent and the host tissues. During the pharyngitis, streptococcal antigens stimulate an antibodyresponse which cross-reacts with a variety of antigens in cardiac tissue. With successive streptococcalinfections, the titre of antibodies rises and the patient has recurrent episodes of ARF and progressivecardiac damage. The level of cardiac-reactive antibodies correlates with the clinical activity of therheumatic fever. Eventually the damaged cardiac tissue may provide antigens to stimulate theauto-immune antibody response and perpetuate the cycle of tissue damage.

There is a wide range of cross reactivity between streptococcal antigens and the heart, including

cardiac myosin and streptococcal M-protein, a surface protein which is the target of opsonicantibodies


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'molecular mimicry', which refers to the sharing of antigenic determinants by the initiating infectiousagent and the host tissues. During the pharyngitis, streptococcal antigens stimulate an antibodyresponse which cross-reacts with a variety of antigens in cardiac tissue. With successive streptococcalinfections, the titre of antibodies rises and the patient has recurrent episodes of ARF and progressivecardiac damage. The level of cardiac-reactive antibodies correlates with the clinical activity of therheumatic fever. Eventually the damaged cardiac tissue may provide antigens to stimulate theauto-immune antibody response and perpetuate the cycle of tissue damage.

There is a wide range of cross reactivity between streptococcal antigens and the heart, including

cardiac myosin and streptococcal M-protein, a surface protein which is the target of opsonicantibodiesmyocardial sarcolemma and streptococcal membrane proteinsheart valve glycoprotein and hyaluronate in the capsule of streptococci

Immunopathology and T cell recognition

Immunoglobulin and complement are deposited in the heart during acute carditis, suggesting theauto-antibodies may contribute to the cardiac damage. However, the characteristic histologicalfeature of rheumatic carditis is a mononuclear cell infiltrate, predominantly of T cells including bothCD4+ and CD8+ T cells. Lymphocytes from patients with ARF do react with streptococcal membraneantigens. Further, patients with acute and chronic RF have high titres of high affinity IgG anti-cardiacantibodies. This type of antibody response requires T cell help (see PBL 1.07, lecture 2), indicatingthat T cells also participate in the auto-immune response. This would require shared peptidedeterminants between streptococci and cardiac tissue, and recently cross-reactive auto-epitopesbetween the M-protein and cardiac myosin have been demonstrated.

Why do a minority of infected individuals develop Rheumatic Fever?

Given the wide-spread crossreactivity between Group A streptococci and the heart, why do so fewpeople develop ARF? There is clearly an individual susceptibility to develop ARF and this is due in partto the genetic control of the host immune response. In some subjects this control is influenced by theHLA genes, as HLA-DR2 and HLA-DR4 are associated with ARF in certain populations, however otherundefined genes must also be involved.

Although the mechanism of chorea is not resolved, this may also be a manifestation of molecularmimicry leading to auto-immune tissue damage. Sera from patients with active chorea contain IgGantibodies which react with neuronal antigens in the caudate and subthalamic nuclei, the basalganglia involved in chorea.

References


Author: Professor Warwick Britton, Medicine

LEARNING TOPIC - Lifestyle modification in vascular disease

Lifestyle modification of people with vascular disease is an essential component of secondaryprevention.

Cigarette smoking, poor dietary habit and inactivity are the major modifiable lifestyle risk factors.

In diabetes which adversely affects vascular disease, lifestyle modification will aid weight loss andimprove blood sugar control reducing vascular complications.

The doctor's role is to identify, assess, prioritise and initiate appropriate changes of these risk factorswhile being mindful of the psychosocial issues that may impede the process.

A number of approaches are available to facilitate lifestyle modification:

Communication skills are important in:

Utilising the doctor-patient relationship.Distributing and explaining appropriate patient education material including kits, leaflets, tapes,videos, phone support services provided by Government agencies, the National HeartFoundation, pharmaceutical firms and support groups.Enlisting the assistance of family members, carers and significant others, eg educating the wifeif she is the family cook, giving the patient the responsibility to walk the dog.

Allied health professionals:

Paramedical eg. dietitians, psychologists, physiotherapists.


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Communication skills are important in:

Utilising the doctor-patient relationship.Distributing and explaining appropriate patient education material including kits, leaflets, tapes,videos, phone support services provided by Government agencies, the National HeartFoundation, pharmaceutical firms and support groups.Enlisting the assistance of family members, carers and significant others, eg educating the wifeif she is the family cook, giving the patient the responsibility to walk the dog.

Allied health professionals:

Paramedical eg. dietitians, psychologists, physiotherapists.Medical specialist units eg shared care programs, smoking cessation clinics, cardiacrehabilitation units, obesity clinics.Community resources eg. National Heart Foundation, Public Health Units, Alcoholics Anonymous,smoking cessation programs eg Smokescreen.Commercial enterprises eg. Gutbusters, Weight Watchers, the local gym, various sporting andactivity clubs.

Pharmaceutical agents:

These may be used as an adjunct to lifestyle modification eg

Nicotine replacement therapyDexfenfluramine hydrochloride as an appetite suppressant in a small subgroup of obesepatients.

The person with vascular disease is most likely to achieve and maintain lifestyle changes under thecare of a family General Practitioner because of the GP's unique and ongoing relationship with thepatient and the insight he/she has into the patient's biopsychosocial situation. The treating specialisthas an important role in providing positive reinforcement of lifestyle changes, and encouraginginitiation of these at point of contact when a patient is amenable to initiatory lifestyle change.

References



Brownell KD, Cohen LR. Adherence to dietary regimens. 2: Components of effective interventions.Behavioural Medicine 1995 Winter; 20 (4):155-64.

Oldenburg B, Owen N, Gomel M, Graham-Clarke P. Lifestyle change and cardiovascular disease.Australian Family Physician Vol. 21 August 1992; 21(8): 1137-1144.

Mendelsohn C. Smokescreen for 1990s: a new approach to cessation. Australian Family Physician.1994 23(5): 841-848.

New South Wales. Dept. of Health, 1996, Physical activity and health : a special communication fromthe Chief Health Officer, 2nd ed., State Health Publication No. (HP) 950129

Exercise for people with heart disease. National Heart Foundation, NSW Division.

National Heart Foundation of Australia, 1995, Exercise for people with heart disease : guidelines forthe prescription and conduct of non-medically supervised, community-based exercise programsed.,National Heart foundation, [Surry Hills, N.S.W.]

Author: Dr David Lim, Medicine

LEARNING TOPIC - Long term management of childhood cardiac disease

The course of congenital heart disease is influenced largely by its severity (impact on normalcardiovascular physiology) and the medication and surgical procedures used to treat it whennecessary.

Differentiation of the consequences of these management strategies is important.

The general outcome for unoperated patients with significant left to right shunts and right to leftshunts, should be differentiated from the lesser range of problems for patients with minor,haemodynamically unimportant lesions.

When surgery is required issues such as surgical myocardial scar, the fate of the cardiac 'prosthetics',myocardial or valve dysfunction, and incompletely corrected lesions arise in latter followup.


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The course of congenital heart disease is influenced largely by its severity (impact on normalcardiovascular physiology) and the medication and surgical procedures used to treat it whennecessary.

Differentiation of the consequences of these management strategies is important.

The general outcome for unoperated patients with significant left to right shunts and right to leftshunts, should be differentiated from the lesser range of problems for patients with minor,haemodynamically unimportant lesions.

When surgery is required issues such as surgical myocardial scar, the fate of the cardiac 'prosthetics',myocardial or valve dysfunction, and incompletely corrected lesions arise in latter followup.

An approach to primary care management of these patients may need to take this into account.

Consequences of unoperated congenital heart diseaseviz: cyanosis, volume load, congestive cardiac failure, paradoxical embolus, polycythaemia,stroke, brain abscess, ventricular dysfunction, arrhythmia, bacterial endocarditisprophylaxis.

Consequences of surgical management of congenital heart disease.Practical advice for patients and families after management of congenital heart disease.

References



Relevant sections of general Paediatric text books will overview these issues and should be read first.

More detailed discussions can be found in:

Jordan, Scott. Heart Disease in Paediatrics. 1989.

Moss, A. J., et al., 2001, Moss and Adams' heart disease in infants, children, and adolescents, includingthe fetus and young adult, 6th ed., Lippincott Williams & Wilkins, Philadelphia ; London. [Available asan E-Book]

Garson, A., 1997, The science and practice of pediatric cardiology, 2nd ed., Williams & Wilkins,Baltimore

Jacobs, M. L. and W. I. Norwood, 1992, Pediatric cardiac surgery : current issues., Butterworth-Heinemann, Boston

Jacobs, Norwood. Paediatric Cardiac Surgery - Current Issues. Butterworth-Heineman, 1992.

Wilson, Neutze. Adult congenital heart disease: principal and management guidelines. Aust & NZ JMed 1993; 23(6): 697-705.

Bethesda Conference. Congenital Heart Disease after Childhood: An expanding patient population.JACC 1991; 18(2): 311-342.

Kaplan. Bacterial endocarditis prophylaxis - tradition or necessity . Am J Cardiol 1986; 57(6):478-479.

Awadallah et al. The changing pattern of infective endocarditis in childhood . Am J Cardiol1991; 68(1): 90-94.

Wilson, W. et al. Prevention of Infective Endocarditis. Guidelines From the American HeartAssociation. A Guideline From the American Heart Association Rheumatic Fever, Endocarditis, andKawasaki Disease Committee, Council on Cardiovascular Disease in the Young, and the Council onClinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and the Quality of Care andOutcomes Research Interdisciplinary Working Group. Circulation . 2007 online Apr 19

Author: Clinical Associate Professor Gary Sholler, Paediatrics and Child Health

LEARNING TOPIC - Medicolegal issues in information-giving

Autonomy"The fundamental principle underlying consent is said to be a right of self-determination: theprinciple, or value choice, of autonomy of the person ... It is an ethical principle which is simplyreflected in legal rules because our law has been developed by judges sensitive to the practicalapplication of generally held community ethical principles (Kirby, M. (1983) "Informed consent: whatdoes it mean?" Journal of Medical Ethics 9:69, at page 70).


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LEARNING TOPIC - Medicolegal issues in information-giving

Autonomy"The fundamental principle underlying consent is said to be a right of self-determination: theprinciple, or value choice, of autonomy of the person ... It is an ethical principle which is simplyreflected in legal rules because our law has been developed by judges sensitive to the practicalapplication of generally held community ethical principles (Kirby, M. (1983) "Informed consent: whatdoes it mean?" Journal of Medical Ethics 9:69, at page 70).

Giving informationThe giving of information to patients is an ethical obligation and a legal requirement, and relates tothe concept of autonomy, that is, enabling the individual to control their own life. The term 'informedconsent' clearly specifies that consent to a medical procedure needs to be based on adequateinformation.

Valid and Informed consentInformed consent is not synonymous with valid consent, because the requirement that consent beinformed is only one aspect of a valid consent. The individual should have the legal capacity to giveconsent, be in a situation where consent may be given freely, without any duress, force, fraud, deceitor coercion, and have sufficient information to make an informed and enlightened decision.

Three areas of law are relevant to informed consent - (1) the crime of battery, (2) the tort of trespasswhich includes assault and battery, and (3) the tort of negligence. Practically, the issue is raisedusually within the arena of the civil law or torts. Trespass is a general term for several causes ofaction, the most relevant here being assault and battery. A battery is an intentional touching ofanother person without consent of that person and without lawful excuse; an assault is theintentional creation in another person of an apprehension of imminent, harmful or offensive contact.Negligence is relevant where it can be shown that there was an obligation on the part of thepractitioner to provide certain information, and that if the information had been given to the patientthat the patient would not have consented to the procedure being carried out.

The nature of the informationThe requirements for the type and amount of information to be disclosed vary with the circumstances.Ultimately the courts have reserved the right to determine what is reasonable. The patient should betold the diagnosis, the alternative treatments, and what the practitioner recommends and why. Theinformation given to the patient must encompass an adequate explanation of the proposed procedure,and be couched in language that the patient can comprehend. Giving a patient a pamphlet may well beinsufficient, particularly if there is no follow-up to ensure the patient could read and understand thepamphlet, and had no further questions. Medical jargon should be avoided. Imprecise terminologywhich may have different subjective interpretations (such as, 'rare', 'often', and 'not serious') shouldbe avoided, in favour of precise description of risks and probabilities (where they are available). Thecourts have implied that the more invasive the procedure, or the graver the consequences, the greatershould be the level of disclosure. Risks such as risk of death, disability and other seriousconsequences should be disclosed, as should information about possible benefits of a procedure.Other serious consequences such as effect on work, and time required for recuperation, should bedisclosed.

As a rule of thumb, large risks of minor harm and small risks of major harm should be disclosed andespecially if there is anything to indicate that a patient would be very concerned about any particularoutcome.

A valid consent is not required in an emergency, because the courts have presumed that anunconscious patient in a life-threatening situation would have consented to treatment. Furthermore,this presumption is in accordance with community values.

If a patient cannot give a valid consent owing to temporary or permanent disability, recourse shouldbe made to obtaining third party consent, consistent with the provisions of the Guardianship Act 1987(NSW) (see Learning Topic on Guardianship).

Consent formsA valid consent form needs to contain details of the actual procedure to be performed. The signedconsent form does not provide proof that the patient consented, but is merely evidence that he or shesigned the particular form. The signature itself does not prove that the patient understood theinformation given, or the nature and effect of the procedure. Consent must be operative at the timethe procedure is performed, and it is important for the consent form to be signed as close as possibleto the time the procedure is performed. The patient's ability to give valid consent should not becompromised by the effects of pre-operative medication, for example.

It is doubtful whether a patient may waive his/her right to the information necessary to make aninformed and valid decision. If a patient stated that he/she did not want to know what was going to


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Consent formsA valid consent form needs to contain details of the actual procedure to be performed. The signedconsent form does not provide proof that the patient consented, but is merely evidence that he or shesigned the particular form. The signature itself does not prove that the patient understood theinformation given, or the nature and effect of the procedure. Consent must be operative at the timethe procedure is performed, and it is important for the consent form to be signed as close as possibleto the time the procedure is performed. The patient's ability to give valid consent should not becompromised by the effects of pre-operative medication, for example.

It is doubtful whether a patient may waive his/her right to the information necessary to make aninformed and valid decision. If a patient stated that he/she did not want to know what was going tohappen and did not want to make the decision, but preferred the doctor to make the decision, apractitioner who acted upon this statement would be unwise. Waiving the important and fundamentalright to autonomy in decision making about one's own body is so significant that it would bepreferable for the waiver to be written, and for independent corroboration to be obtained that thepatient prefers a third party to make the decision. If the patient persists in refusing to acceptinformation or decision-making responsibility, recourse may have to be made to the GuardianshipTribunal. The medical practitioner cannot assume the right to make decisions on the part of thepatient, except in an emergency.

References



It would be advisable to consult specialist resources on medico-legal issues, particularly thoserelating to the Australian legal system. Useful references include:

Bates PW, Dewdney JC, Australian CCH Health and Medical Law Editors, Health and Medical LawReporter, CCH Australian Ltd, paragraphs 16-900 to 16-970 (Consent) and 17-000 to 17-420(Elements of Consent)

See also - http://www.lawlink.nsw.gov.au/lrc.nsf/pages/ip24chp08NSW Law Reform Commission, 2004, Minors’ consent to medical treatment. Issues paper 24.

Author: Professor Susan Hayes, Medicine

LEARNING TOPIC - Microbiology of endocarditis and rheumatic heart disease

Rheumatic fever and carditis (pericarditis, myocarditis and endocarditis) are sequels to one or moreattacks by certain infectious agents.

Rheumatic fever (RF) is a nonsuppurative acute inflammatory complication of infection due to certainstrains of beta-haemolytic Group A Streptococcus pyogenes. RF is characterised mainly by arthritis,chorea, or carditis (sometimes followed by residual heart disease), alone or in combination. The skin(subcutaneous nodules and erythema marginatum) may also be involved.

RF occurs mostly during school age (peak 5-15years). The incidence of RF is 0.1 to 3% of those withstreptococcal infections. The latent period is 1-5 weeks (av 19 days) between streptococcalpharyngitis and the initial episode of acute RF. The average duration of RF is 3 months or longer.

Carditis is the most significant manifestation of RF. Murmurs are the most frequent clear sign ofcarditis when the patient is first seen. After the acute attack many people are left with damaged heartvalves (rheumatic heart disease). Valve involvement characterised by an acute interstitial valvulitismay cause valvula oedema. Left untreated, valve thickening, fusion, and retraction or otherdestruction of leaflets and cusps may occur, leading to stenotic or regurgitant functional changes.Abnormal or damaged valves are most susceptible to infection and colonisation e.g., by alphahaemolytic streptococci and cause endocarditis (see below). Recurrent acute attacks of RF frequentlycause more damage to the heart valves.

Antibiotics will not modify an acute RF attack, due to cross-reacting autoimmunity, nor affect thesubsequent development of carditis. However, a recommended regimen of antibiotics is prescribed toeradicate any remaining group A streptococci. A treatment goal is to suppress inflammation whileavoiding a rebound. Aspirin or another NSAID is the first choice.

Endocarditis - inflammation of the endocardium (membrane lining the chambers of the heart andcovering the cusps of the various valves) - is caused directly by microbial colonisation of theendocardium or indirectly by RF. Infective endocarditis is due to organisms being physically present,


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Abnormal or damaged valves are most susceptible to infection and colonisation e.g., by alphahaemolytic streptococci and cause endocarditis (see below). Recurrent acute attacks of RF frequentlycause more damage to the heart valves.

Antibiotics will not modify an acute RF attack, due to cross-reacting autoimmunity, nor affect thesubsequent development of carditis. However, a recommended regimen of antibiotics is prescribed toeradicate any remaining group A streptococci. A treatment goal is to suppress inflammation whileavoiding a rebound. Aspirin or another NSAID is the first choice.

Endocarditis - inflammation of the endocardium (membrane lining the chambers of the heart andcovering the cusps of the various valves) - is caused directly by microbial colonisation of theendocardium or indirectly by RF. Infective endocarditis is due to organisms being physically present,unlike RF, that predisposes to colonisation. The disease can be either acute or chronic. Whilst almostall bacteria and many fungi can infect/colonise the endocardium the majority of cases (>80%) arecaused by streptococci and staphylococci - many derived from normal flora e.g., from minor trauma tothe oropharynx, gastrointestinal tract and genitourinary tract.

As the bacteria colonise the endocardium, they form 'vegetations' that interfere with valve function.They break off easily to form arterial emboli. The interval between colonisation of the endocardiumand the onset is 2 weeks. Untreated, death can occur in about 6 weeks. The initial symptoms includelow grade fever, anorexia, fatigue anaemia and splenomegaly.

Blood culture is most important in the laboratory diagnosis.

Treatment includes combination antibiotic therapy for at least 14 days. Antibiotic regimen is based onspecies sensitivity and minimum bactericidal concentrations (MBC) in the blood maintained.Anticoagulation with heparin is contraindicated.

Prevention of endocarditis in patients with heart-valve damage or a heart murmur can be helped byantibiotics before medical/dental procedures as well as by the maintenance of good oral hygiene.

Author: Dr Vitali Sintchenko, Infectious Diseases

LEARNING TOPIC - Normal ECG

The spread of action potentials through the heart leads to electrical changes on the body surfacewhich can be recorded as the electrocardiogram. At this stage you need to be familiar with the

appearance of the normal ECGthe nomenclature of the ECGunderstanding how electrical activity spreads through the heartthe concept of the electrical axisthe nomenclature of the 12 leads used for clinical ECGshow the electrical axis is determined from a 12 lead ECG and why it is useful.

Electrical activity normally arises in the sinoatrial node (SAN) and then spreads radially out from theSAN across both atria. When part of the atria is polarised at the resting potential (-80 mV) andanother part is depolarised to the peak of the action potential (+ 30 mV), the resulting voltagegradients cause current flow.

An important principle is that all current flow at one time can be represented by a single currentwith a certain magnitude and direction (the vector sum of currents) and the angle between thiscurrent and an agreed system of axes is called the electrical axis at that moment.A second principle is that electrode pairs along the line of that axis will see the largest voltagechange while those perpendicular to the axis will record no voltage difference. Thus by having aseries of electrode pairs arranged around the vertical plane (the limb leads) one can determinethe electrical axis in the vertical plane. Similarly the chest leads are arranged around ahorizontal plane and determine the direction of the electrical axis in that plane (called rotation).

These considerations determine the size of the P wave produced by atrial depolarisation and the leadsin which it is most prominent. Similar but more complex considerations can explain the form ofventricular depolarisation (the QRS wave) and ventricular repolarisation causes the T wave.

The PQ interval represents the time taken for conduction from the SAN (i) across the atria, (ii)through the atrioventricular node, and (iii) through the fast conduction system of the ventricles to theventricular muscle. When this time is elongated or irregular it suggests some defect in normalconduction. The QT interval represents the duration of the ventricular action potential and should getshorter during exercise.

Value of the electrical axis. A simple example is left ventricular hypertrophy (enlargement) whichoccurs in systemic hypertension as the left side of the heart increases to deal with an increased work


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These considerations determine the size of the P wave produced by atrial depolarisation and the leadsin which it is most prominent. Similar but more complex considerations can explain the form ofventricular depolarisation (the QRS wave) and ventricular repolarisation causes the T wave.

The PQ interval represents the time taken for conduction from the SAN (i) across the atria, (ii)through the atrioventricular node, and (iii) through the fast conduction system of the ventricles to theventricular muscle. When this time is elongated or irregular it suggests some defect in normalconduction. The QT interval represents the duration of the ventricular action potential and should getshorter during exercise.

Value of the electrical axis. A simple example is left ventricular hypertrophy (enlargement) whichoccurs in systemic hypertension as the left side of the heart increases to deal with an increased workload. Because the left side of the heart is bigger, the net current flow to the left is bigger and thisshifts the electrical axis in the vertical plane to the left (anti-clockwise).

You also need to be familiar with all the events of the cardiac cycle and understand the timing of theatrial and ventricular contraction, the opening and closing of the valves and the way each of theserelates to the ECG.

Clinically the main value of the ECG is in the diagnosis of arrhythmias, ischaemic heart disease andinfarcts. Many other cardiac conditions also have identified ECG abnormalities.

References



LEARNING TOPIC - Oedema

Oedema is a common symptom and sign with many disparate causes. It means accumulation of fluidin the interstitial space, and to understand how it occurs it is necessary to understand the balance offorces across the capillary wall. The interstitial space is the part of the extracellular space which isoutside the capillaries and between the cells.

To distinguish oedema from other cause of tissue swelling, eg fat, tumours, chronic inflammation andfibrosis, the classic test is that oedema 'pits', ie firm pressure with a finger leaves a dent which takesa minute or so to obliterate. The distribution of the oedema is often diagnostic and can involve theankles, legs, sacrum, scrotum, peritoneum, pleural cavities, the lung tissue (pulmonary oedema isparticularly serious), the face, lips, glottis and vocal cords (may cause asphyxiation in severe foodallergies), the brain etc. The distribution of oedema is affected by the patients position, eg bedriddenpatients tend to have sacral oedema.

The forces tending to cause fluid to cross the capillary wall (from plasma to interstitial space) werefirst described by Starling (who also discovered Starling's Law of the Heart and the first hormone,secretin). One factor which favours movement of fluid out of the capillary is the hydrostatic pressurewithin the capillary, and this is offset by the hydrostatic pressure of the interstitial space itself (oftenclose to zero). While the mean pressure in the capillaries is around 25 mmHg, it is higher at thearterial end and lower at the venous end. Because molecules with very large molecular weights do noteasily move through the capillary wall, these are retained in the capillary and exert a colloid osmoticpressure which tends to attract fluid into the capillary. It is a useful exercise in physical chemistry toconvert the known amounts of impermeable proteins in blood into their molar concentration and theninto the osmotic pressure they exert (using the gas laws). The answer is that the plasma proteins(chiefly albumin) exert a colloid osmotic pressure of about 20 mmHg which attracts fluid into thecapillary. This is offset by the colloid osmotic pressure of any proteins within the interstitial space.The rate at which fluid crosses the capillary wall is then the sum of these four pressures multiplied bythe capillary permeability. Finally, excess fluid in the interstitial space can often be removed by thelymphatics.

Any of the above factors can be disturbed. Hydrostatic pressure in the capillary (and all other blood

compartments) is increased when Na and H 2 0 are retained, as in heart failure and steroid overdose,and can cause massive oedema over the ankles, legs and sacrum. An important distinction is thatL-sided heart failure tends to cause pulmonary oedema, whereas R-sided heart failure tends to causesystemic oedema. Reduced serum albumin is another large category causing generalised oedema andcan be caused by malnutrition (kwashiorkor) or malabsorption of proteins, loss of proteins as in renalfailure or nephrotic syndrome or failure to synthesis albumin which occurs in liver disease. Increasedcapillary permeability occurs in many allergic reactions and is probably caused by histamine releaseeg bee stings, food allergies and these can cause dangerous but short lived oedemas. Finally,blockage of lymphatic channels by infection (filariasis leading to elephantiasis) or by tumour, surgeryor radiation damage can also result in oedema.


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compartments) is increased when Na and H 2 0 are retained, as in heart failure and steroid overdose,and can cause massive oedema over the ankles, legs and sacrum. An important distinction is thatL-sided heart failure tends to cause pulmonary oedema, whereas R-sided heart failure tends to causesystemic oedema. Reduced serum albumin is another large category causing generalised oedema andcan be caused by malnutrition (kwashiorkor) or malabsorption of proteins, loss of proteins as in renalfailure or nephrotic syndrome or failure to synthesis albumin which occurs in liver disease. Increasedcapillary permeability occurs in many allergic reactions and is probably caused by histamine releaseeg bee stings, food allergies and these can cause dangerous but short lived oedemas. Finally,blockage of lymphatic channels by infection (filariasis leading to elephantiasis) or by tumour, surgeryor radiation damage can also result in oedema.

References



LEARNING TOPIC - Overview of cardiovascular function

The cardiovascular system consists of a pump and a complex series of tubes. Its function is to supplyever cell of the body with its needs (O

2 , glucose, amino acids, lipids, vitamins, hormones, heat,

inorganic ions, H 2 O, .. etc.) and to remove waste products (CO

2 , H

2 O, lactate, protons, urea, heat,

.. etc. The supply to each cell should be in accordance with its needs.

There are ~10 14 cells in the body so supplying each with its needs, which are different for each celltype and change with cell activity, is a formidable task. While this complex task generally continuessuccessfully without any conscious activity on our part, inevitably there are conflicts from time totime and priorities have been set (by evolution) which determine which cells are highest priority andhave a protected circulation during times of stress.

If the blood supply to the brain ceases for > 10s we lose consciousness (potentially a disaster inevolutionary terms). Consequently supplying blood to the brain is the highest priority and, becauseblood supply to the brain requires the heart, blood supply to the heart is equally high priority. If bloodsupply to the brain ceases for more than ~ 10 min there is likely to be permanent brain damage evenif flow is restored.

To understand the circulation some understanding of the underlying physical principles is valuable.Two processes are central; diffusion and flow through tubes. Diffusion is the process by whichmolecules move down their concentration gradient powered by the random thermal motion ofmolecules. Thus if a cell uses O

2 , the concentration of O

2 in the cell decreases, and the increasing

inward concentration gradient causes additional O 2 to diffuse into the cell. In general the rate of

diffusion is proportional to the concentration gradient, to the area involved and to the diffusioncoefficient of the molecule and inversely proportional to the square of the distance involved. Althoughthe mathematics of diffusion are complex a very simple rule of thumb is that diffusion over a distance

of 1 m is near complete in 1 ms. Because of the inverse square law, diffusion over 1 mm (10 3 ! m)

takes (10 3 ) 2 ms or 1000s or 15 min. Diffusion over 1 m takes 10 12 ms or 30 years. These physicalprinciples dominate the design of cells and the need for a circulation to supply any region greater than10-100 !m. Thus single cells do not require a circulation (diffusion is sufficient) whereas all largemulticellular organs require a circulation.

The second process, flow in pipes, is dealt with extensively in physiology texts. Flow through a tube is

proportional to the pressure gradient across the region of interest and to the (radius) 4 and inverselyproportional to the length of the pipe and the viscosity of the solution. Again these physical factorsare critical to the design of a series of pipes which transport blood sufficiently close to every cell toenable diffusion to carry molecules to (and from) the cell. The regulation of flow to the region of asmall group of cells is determined by the radius of the pipe carrying blood to the region and thisradius is regulated by a series of mechanism which will be explored in the Blood flow to tissueslecture.




2 , H



There are ~10 14 cells in the body so supplying each with its needs, which are different for each celltype and change with cell activity, is a formidable task. While this complex task generally continuessuccessfully without any conscious activity on our part, inevitably there are conflicts from time totime and priorities have been set (by evolution) which determine which cells are highest priority and


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radius is regulated by a series of mechanism which will be explored in the Blood flow to tissueslecture.




2 , H



There are ~10 14 cells in the body so supplying each with its needs, which are different for each celltype and change with cell activity, is a formidable task. While this complex task generally continuessuccessfully without any conscious activity on our part, inevitably there are conflicts from time totime and priorities have been set (by evolution) which determine which cells are highest priority andhave a protected circulation during times of stress.

If the blood supply to the brain ceases for > 10s we lose consciousness (potentially a disaster inevolutionary terms). Consequently supplying blood to the brain is the highest priority and, becauseblood supply to the brain requires the heart, blood supply to the heart is equally high priority. If bloodsupply to the brain ceases for more than ~ 10 min there is likely to be permanent brain damage evenif flow is restored.

To understand the circulation some understanding of the underlying physical principles is valuable.Two processes are central; diffusion and flow through tubes. Diffusion is the process by whichmolecules move down their concentration gradient powered by the random thermal motion ofmolecules. Thus if a cell uses O

2 , the concentration of O

2 in the cell decreases, and the increasing

inward concentration gradient causes additional O 2 to diffuse into the cell. In general the rate of

diffusion is proportional to the concentration gradient, to the area involved and to the diffusioncoefficient of the molecule and inversely proportional to the square of the distance involved. Althoughthe mathematics of diffusion are complex a very simple rule of thumb is that diffusion over a distance

of 1 m is near complete in 1 ms. Because of the inverse square law, diffusion over 1 mm (10 3 ! m)

takes (10 3 ) 2 ms or 1000s or 15 min. Diffusion over 1 m takes 10 12 ms or 30 years. These physicalprinciples dominate the design of cells and the need for a circulation to supply any region greater than10-100 !m. Thus single cells do not require a circulation (diffusion is sufficient) whereas all largemulticellular organs require a circulation.

The second process, flow in pipes, is dealt with extensively in physiology texts. Flow through a tube is

proportional to the pressure gradient across the region of interest and to the (radius) 4 and inverselyproportional to the length of the pipe and the viscosity of the solution. Again these physical factorsare critical to the design of a series of pipes which transport blood sufficiently close to every cell toenable diffusion to carry molecules to (and from) the cell. The regulation of flow to the region of asmall group of cells is determined by the radius of the pipe carrying blood to the region and thisradius is regulated by a series of mechanism which will be explored in the Blood flow to tissueslecture.

Generally in the circulation evolutionary design has ensured that diffusion is sufficient for the supplyof molecules to cells and, with a few exceptions, it is not under physiological control. In contrastsupply of blood to the tissues changes continuously to meet the "supply to each cell according to itsneeds" constraint and is central to understanding the regulation of the blood supply. To a goodapproximation the pressure in the collection vessels (venules and veins) is atmospheric (called zero)while the pressure in the distribution vessels (arteries and arterioles) is maintained at a more or lessconstant level (the arterial pressure). This means that the flow to the exchange vessels (thecapillaries from which diffusion then carries molecules to the cells) depends only on the radius of the

vessel supplying them. Roughly there are 10 10 capillaries so the 10 4 cells supplied by each capillaryall receive a similar blood supply though they can vary their supply by diffusion.

One of the many complications to this system is the effects of hydrostatic pressures on the humancirculation and particularly the changes associated with posture. The properties of the pump areunaffected by postural changes and by good fortune arterial pressure is generally measured in theupper arm which is almost exactly at the level of heart. When we become upright, ~1.3 m of blood (~100 mm Hg) is added to the arterial pressure in the foot. Exactly the same happens to venouspressure, so the gradient of pressure across the tissues of the foot is unaffected and, simplistically,blood flow to the foot is unaffected. But vessels also dilate when the pressure inside them increasesand these lead to accumulation of blood particularly in the more compliant vessels which are theveins.

You should also revise the physics of measuring blood pressure using a sphygmomanometer and cuff.

The elementary anatomy of the cardiovascular system, names and distributions of the major arteriesand veins and chambers of the heart, are essential background.

References

Berne, R. M., 2004, Physiology, 5th ed., Mosby, St. Louis. Chapters 14 (Overview of the heart and


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blood flow to the foot is unaffected. But vessels also dilate when the pressure inside them increasesand these lead to accumulation of blood particularly in the more compliant vessels which are theveins.

You should also revise the physics of measuring blood pressure using a sphygmomanometer and cuff.

The elementary anatomy of the cardiovascular system, names and distributions of the major arteriesand veins and chambers of the heart, are essential background.

References

Berne, R. M., 2004, Physiology, 5th ed., Mosby, St. Louis. Chapters 14 (Overview of the heart andblood vessels) and 18 (Haemodynamics) and 20 (Microcirculation and Lymphatics) provide anexcellent coverage of these issues.


LEARNING TOPIC - Overview of congenital heart disease

Congenital Heart Disease is one of the most common forms of serious congenital abnormality. Itsrange, however, is wide and many patients may have minor abnormalities not likely to produce eitherovert or occult damage to the patient.

Congenital heart lesions are quite unlike the pathology seen in the adult.

The wide range of congenital heart abnormalities can be divided into broad subcategories of acyanoticand cyanotic heart disease. Alternate approaches may consider physiology of left to right shunts, andobstructive lesions. These may occur independently or in combination (such as in this case).

The problems of differentiating congenital cardiac pathology from the normal heart arises often inyoung children and babies since a cardiac murmur, commonly seen arising from the normal heart of achild, may raise suspicions when its character is unusual.

Early and appropriate management can be life saving or avoid the long term damaging sequelae ofunrecognised abnormality. This management will usually be delivered by a paediatric cardiologist andpaediatric cardiac surgeon, but initial recognition will depend on the primary care physician in manycases.

Heart and Great Vessel Anatomy

An understanding of normal cardiac anatomy will prepare the student to appreciate the variety ofstructural lesions possible, without needing to be familiar with each one. Each area of the heart(alone or in combination) may be affected by maldevelopment.

Physiology of cardiac shunts and vascular resistance

These lesions will often have associated septal defects allowing blood to cross between thepulmonary and systemic circulations. This movement of blood, or 'shunt', will be dictated by a numberof factors including the size of the defect and the 'downstream' resistance to flow. In many importantlesions resistance may be either at a structural level or at the level of vascular resistance (especiallyin the pulmonary circulation). The issue of PVR is particularly important to understanding the clinicalpresentation and course of young infants with ventricular septal defect and other types of 'left to rightshunt' lesions.

Incidence and range of congenital heart disease and congestive cardiac failure in infants

Once these concepts are recognised the incidence and range of congenital heart abnormalities can bebetter appreciated, and the causes of congestive heart failure in babies, and its time of presentation,be understood.

References



Relevant sections of general Paediatric text books will often overview these issues.


Jordan, Scott. Heart Disease in Paediatrics. London: Butterworths, 1989.

Moss, A. J., H. D. Allen, et al., 2001, Moss and Adams' heart disease in infants, children, and


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Relevant sections of general Paediatric text books will often overview these issues.


Jordan, Scott. Heart Disease in Paediatrics. London: Butterworths, 1989.

Moss, A. J., H. D. Allen, et al., 2001, Moss and Adams' heart disease in infants, children, andadolescents, including the fetus and young adult, 6th ed., Lippincott Williams & Wilkins, Philadelphia ;London. [Available as an E-Book]

Garson, A., 1997, The science and practice of pediatric cardiology, 2nd ed., Williams & Wilkins,Baltimore

Anderson, R. H., 2002, Paediatric cardiology, 2nd ed., Churchill Livingstone, London


LEARNING TOPIC - Pathogenesis of hypertension

Hypertension is divided into primary or essential hypertension and secondary forms of hypertension.It is still not clear whether it is a single disorder, or a disorder with several subsets of patients havingvarying 'causes' of hypertension. Factors in the pathogenesis of hypertension relate to (a) thoseimportant in regulating normal blood pressure such as the heart, the kidneys, vascular diameter andthe venous system and (b) how these systems are influenced by the autonomic nervous system,various circulating hormones (such as catecholamines, ANP, renin, aldosterone and other steroids)and numerous local hormones or autacoids (eg. prostaglandins, nitric oxide and endothelin). (c)Various lifestyle and dietary factors, including exercise, ethanol intake and dietary sodium level.

Even though blood pressure is chiefly determined by both peripheral resistance and cardiac output,the division of hypertension into volume or constrictor subsets has been unrewarding, as all patientstend eventually to have elevation of peripheral resistance and normal cardiac output. Thus inhypertension, the increase in blood pressure results from constriction of small arteries and arterioles.This leads to an increased resistance to flow. The increased peripheral resistance may result fromeither the presence of increased stimuli leading to excess vasoconstriction (increased vascularreactivity) or from intrinsic abnormalities within the resistance vessels that cause an increasedresponse to normal stimuli, or from a combination of the two mechanisms.

Abnormalities relating to sympathetic nerve endings (pre and postsynaptic) have been described inanimal models of hypertension but there is still considerable debate as to their importance in humanhypertension. Similarly, catecholamines have been clearly implicated only in the genesis ofhypertension with phaeochromocytoma. The renin-angiotensin-aldosterone system (RAAS) has beenextensively studied. Hypertension associated with severe unilateral renal artery stenosis,aldosterone-secreting tumours of the adrenal cortex, renin secreting tumours, oral contraceptive pilluse or some dialysis-dependent chronic renal failure patients, is commonly due to aberrations in theRAAS.

The kidney deserves special attention, it is both a victim and culprit in the hypertensive process.Recent evidence implicates defective renal sodium excretion as a pivotal hypertensive mechanism.

Hypotheses to explain this include inhibitors of tubular and vascular smooth muscle Na + K + ATPase(and a consequent elevation of intracellular calcium leading to vasoconstriction), congenitally reducednephron numbers (or filtration surface areas) and also heterogeneity within the nephron population.

A rare autosomal, dominantly-inherited form of human hypertension, Liddle's Disease (which is alsocharacterized by hypokalaemia, suppressed aldosterone, response to inhibitors of distal tubularsodium transport but not to mineralocorticoid antagonists) has thrown new light on other yet to beexplored pathogenetic hypertensive mechanisms. Mutations of the aldosterone-regulated and

amiloride-sensitive epithelial Na + channel (ENaC) gene, lead to the constitutive activation of ENaCand cause Liddle's syndrome. The consequent excessive reabsorption of sodium in the distal nephroncauses severe hypertension. Molecular techniques increasingly are uncovering other new mechanismsof hypertension such as that concerning ACE gene polymorphism and 11"-hydroxysteroiddehydrogenase type-2 gene mutations.

References




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sodium transport but not to mineralocorticoid antagonists) has thrown new light on other yet to beexplored pathogenetic hypertensive mechanisms. Mutations of the aldosterone-regulated and

amiloride-sensitive epithelial Na + channel (ENaC) gene, lead to the constitutive activation of ENaCand cause Liddle's syndrome. The consequent excessive reabsorption of sodium in the distal nephroncauses severe hypertension. Molecular techniques increasingly are uncovering other new mechanismsof hypertension such as that concerning ACE gene polymorphism and 11"-hydroxysteroiddehydrogenase type-2 gene mutations.

References



Zanchetti A, Tarazi RC, eds. Pathophysiology of Hypertension: Volume 8. Handbook of Hypertension.Amsterdam: Elsevier, 1986.

Sherwood, L., 2007, Human physiology : from cells to systems, 6th ed., Thomson/Brooks/Cole,Australia

Author: Clinical Associate Professor Adrian Gillin, Medicine

LEARNING TOPIC - Pathophysiology of hypertension

Normal blood pressure regulation is dependent upon total peripheral vascular (arteriolar) resistanceand cardiac output. It appears likely that in systemic hypertension, the persistent elevation of bloodpressure at rest may be due to factors involving an increase in either or both of these haemodynamicvariables. For example a boost in cardiac output may be achieved by fluid retention (as outlinedbelow) or as a response to defective pressure "natriuresis" with sodium retention.

The majority of patients with systemic hypertension (~90%) have no clear underlying causedemonstrable after investigation. Such patients are referred to as having essential hypertension. It isprobable that most of the pathophysiological mechanisms of hypertension in this group will have beenreferred to in Independent Learning Topic 3 "Pathogenesis of Hypertension". Accordingly, in thisLearning Topic there will be emphasis on the pathophysiology of hypertension in those patients inwhom an underlying and sometimes remediable cause is demonstrable. i.e. those patients withsecondary hypertension.

Chronic renal disease

A number of renal diseases of diverse origin can lead to the development of hypertension. Thesediseases include:

Renal ischaemia frequently due to renal artery atherosclerosis, either at its orifice or in its stem.('renovascular hypertension')Chronic renal parenchymal damage following for example, immunological glomerular injury(glomerulonephritis) or recurrent bacterial infections.

In such patients, the alterations in renal perfusion with blood will tend to activate the renin-angiotensin system whereby the enzyme renin released from the juxtaglomerular apparatus convertsthe plasma protein, angiotensinogen (from the liver) to angiotensin:

This is further processed by angiotensin-converting enzyme (ACE) and ACE-peptidases in theendothelial cell membrane to the biologically active vasoconstrictor agent angiotensin II.This mechanism will tend to lead to an increase in the patient's blood pressure and to boostrenal perfusion.

Essential hypertension itself, either when mild to moderate (benign) but especially when very severe(malignant) may lead to structural and functional alterations in the kidney which may activate therenin-angiotensin system.

Adrenal lesions

The adrenal cortex produces hormones such as glucocorticoids and mineralocorticoids which haveeffects on blood pressure. The mineralocorticoid, aldosterone for example affects blood pressurelevels by its effect on salt and water metabolism.

In functional lesions of the adrenal cortex such as adenoma, hyperplasia and carcinoma, the increasedproduction of such hormones tends to lead to secondary hypertension. Aldosterone stimulation is alsoinvolved during activation of the renin-angiotensin system.

Another adrenal lesion capable of producing secondary hypertension is a functional tumour of the


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Adrenal lesions

The adrenal cortex produces hormones such as glucocorticoids and mineralocorticoids which haveeffects on blood pressure. The mineralocorticoid, aldosterone for example affects blood pressurelevels by its effect on salt and water metabolism.

In functional lesions of the adrenal cortex such as adenoma, hyperplasia and carcinoma, the increasedproduction of such hormones tends to lead to secondary hypertension. Aldosterone stimulation is alsoinvolved during activation of the renin-angiotensin system.

Another adrenal lesion capable of producing secondary hypertension is a functional tumour of theadrenal medulla referred to as phaeochromocytoma. This tumour may produce an excessive amountof noradrenaline, a vasoconstrictor compound.

The various lesions referred to above are firmly associated with secondary hypertension. It isprobable that the mechanisms by which they lead to increased peripheral resistance may alsocontribute toward the increased vascular resistance in patients with essential hypertension.

Evidence for renal involvement in essential hypertension includes elevation of plasma renin in somepatients with this disorder and production by the kidney of vasodepressor substances such asprostaglandins and the endothelial relaxant, nitric oxide which may counterbalance the effects of therenin-angiotensin system.

References



The text-book by Kumar et al provides coverage of fundamental concepts in Pathology. Cotran et al issimilar in its provision of fundamentals but is a more comprehensive text. The text by Rubin andFarber is comparable with Cotran et al.

All these texts provide basic correlation of fundamental disease processes and the clinicalabnormalities with which they are associated.

Kumar, V. and S. L. Robbins, 2007, Robbins basic pathology, 8th ed., Saunders/Elsevier, Philadelphia,PA

Kumar, V., A. K. Abbas, et al., 2005, Robbins and Cotran pathologic basis of disease, 7th ed.,Elsevier Saunders, Philadelphia.[Available as a E-Book]

Author: Professor Roger Dampney, Physiology

LEARNING TOPIC - Pathophysiology of ischaemia

Myocardial ischaemia is a pathological condition which occurs when there is insufficient blood flow tomeet the metabolic demands of the beating heart (ischein = to suppress, haemia = blood). Undernormal circumstances blood flow to the myocardium is well matched to the demands of the heart forO

2 and nutrients. As myocardial O

2 demand increases, it must be parallelled by an increase in

myocardial blood flow, because coronary arteriovenous O 2 extraction is near maximal at rest.

The major determinants of myocardial O 2 consumption are: 1) Heart rate 2) Left ventricular (LV) wall

stress (this is dependent on LV volume, and LV afterload or systolic blood pressure) 3) Contractility.Exercise and emotional stress increase all of the determinants of O

2 consumption, and in the normal

heart, coronary blood flow increases up to five fold to meet this demand. When there is anatherosclerotic stenosis in an epicardial coronary artery, it may limit the ability of the coronarycirculation to increase flow. The haemodynamics of stenoses are such that flow limitation duringexercise occurs when 70% of the lumen diameter is obstructed, while a stenosis of 90% will limitflow at rest. Stenoses of <50% lumen diameter do not usually limit flow during exercise.

Ischaemia can therefore result from either a significant fall in coronary blood flow (supply ischaemia),or an increase in myocardial O

2 demand in excess of the diseased coronary circulation ' s ability to

increase flow due to the presence of obstructive coronary artery disease (demand ischaemia). Thusdemand ischaemia typically occurs during exercise in patients with a coronary stenosis of 70% orgreater and is quickly relieved by rest. Supply ischaemia occurs at rest when an artery occludes orsuddenly develops a stenosis of 90% or greater. This usually results from coronary thrombosis whichmay be complete or subtotal, although vasoconstriction or spasm are alternative mechanisms. Ifobstruction occurs more gradually, collaterals may develop and reduce or even prevent ischaemia.


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exercise occurs when 70% of the lumen diameter is obstructed, while a stenosis of 90% will limitflow at rest. Stenoses of <50% lumen diameter do not usually limit flow during exercise.

Ischaemia can therefore result from either a significant fall in coronary blood flow (supply ischaemia),or an increase in myocardial O

2 demand in excess of the diseased coronary circulation ' s ability to

increase flow due to the presence of obstructive coronary artery disease (demand ischaemia). Thusdemand ischaemia typically occurs during exercise in patients with a coronary stenosis of 70% orgreater and is quickly relieved by rest. Supply ischaemia occurs at rest when an artery occludes orsuddenly develops a stenosis of 90% or greater. This usually results from coronary thrombosis whichmay be complete or subtotal, although vasoconstriction or spasm are alternative mechanisms. Ifobstruction occurs more gradually, collaterals may develop and reduce or even prevent ischaemia.Severe supply ischaemia with complete occlusion of an epicardial coronary artery for longer than 30minutes will result in myocardial infarction (myocardial cell death).

Within a few seconds of ischaemia, there are profound metabolic and physiological changes in theaffected region of myocardium. Metabolism switches from aerobic utilisation of fatty acids toanaerobic glycolysis with production of lactic acid. High energy phosphate production falls, and thiscauses failure of both contraction and active relaxation, which can result in elevation of LV

end-diastolic pressure and breathlessness. Because less energy is available for membrane Na + /K +

pump, K + leaks out of cells, raising resting membrane potential and reducing action potential sizeand duration. This produces characteristic ECG changes: ST segment depression with subendocardialischaemia and ST segment elevation with transmural ischaemia. Elevation and depression of STsegments are relative to the isoelectric segments in the TP and PQ periods.

A late event in myocardial ischaemia is the generation of chest pain (angina pectoris). The painproducing stimulus is probably adenosine, and the sensation is carried by sympathetic afferents whichsynapse between spinal segments C8 and T4 producing referred pain in the retrosternal area, typicallyradiating to the left arm or neck. Many attacks of ischaemia, however, are not accompanied by anginalpain (silent ischaemia).

Author: Professor Ben Freedman, Medicine

LEARNING TOPIC - Personality and coronary heart disease

Linkages between personality and diseaseIncreasing evidence supports the view that personality is related to the development of disease andinfluences disease outcomes. Although the research is promising, the methodological issues arecomplex, and there may be multiple causal linkages which can vary across the lifespan and be relatedto individual differences. Many research projects are limited by the factors of time, the disease understudy, emphasis on treatment rather than prevention of disease, the possibility that disease maycause personality changes rather than the other way around, and a research focus upon ill individualsrather than long-term examination of population samples.

PersonalityPersonality refers to the patterns of cognitive, affective, and behavioural dispositions thatcharacterise individuals. Personality patterns are thought to be relatively stable across time andcontext. For an overview of the main approaches to describing personality and theories of personalitydevelopment, it will be useful to read the relevant sections of your text books. There is now fairlybroad consensus that broad classifications of personality can be made on the basis of the 'Big Five'traits: (see the learning topic on Personality and Addiction). Research is also attempting to identifymore specific personality factors that contribute to effectiveness and adaptiveness, influencingsickness and health.

Personality and CHD (coronary heart disease)The linkages between heart disease and 'Type A personality behaviour' have been studied extensively.The key features of the Type A behaviour pattern are: insecurity, hostility, time urgency, impatienceand competitiveness. Friedman and Rosenman first described Type A behaviour on the basis ofstructured interviews in which they observed tense facial and body musculature, rapid bodymovements, explosive conversational speech, and hand or teeth clenching. Since then moreconvenient methods, such as self-report questionnaires, have been used though it seems that they donot measure precisely the same construct. A meta-analysis of prospective studies of Type Apersonality, hostility and coronary heart disease (CHD) found no association between Type Apersonality and CHD; the only significant association was in healthy adult studies where angina wasincluded as an outcome (Myrtek, 2001). Type A personality does not appear to be a robust predictorof CHD across different cultures and socio-economic groups.

Given the inability of measurements of Type A behaviour to predict risk of morbid events following theinitial incidence of CHD, investigative focus has shifted toward identifying those elements of theconstruct most strongly associated with CHD. With more conventional risk factors statistically


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structured interviews in which they observed tense facial and body musculature, rapid bodymovements, explosive conversational speech, and hand or teeth clenching. Since then moreconvenient methods, such as self-report questionnaires, have been used though it seems that they donot measure precisely the same construct. A meta-analysis of prospective studies of Type Apersonality, hostility and coronary heart disease (CHD) found no association between Type Apersonality and CHD; the only significant association was in healthy adult studies where angina wasincluded as an outcome (Myrtek, 2001). Type A personality does not appear to be a robust predictorof CHD across different cultures and socio-economic groups.

Given the inability of measurements of Type A behaviour to predict risk of morbid events following theinitial incidence of CHD, investigative focus has shifted toward identifying those elements of theconstruct most strongly associated with CHD. With more conventional risk factors statisticallycontrolled (e.g. heredity, obesity, diet and smoking) research has indicated that expressive hostility,particularly antagonistic interactions with others (anger-out), appears most strongly associated withCHD (Myrtek, 2001). Other hostility related constructs, including cynical mistrust, potential forhostility, and suppressed resentment (anger-in) have also been found to predict CHD mortality andmorbidity. Other clusters of psychological variables that are currently being investigated with respectto multiple disease outcomes are emotional suppression, depressive symptoms, and the adoption of apessimistic or fatalistic attitude to life and health.

The term 'Type D' (distressed personality) has entered the literature recently, describing thecombination of negative affectivity and social inhibition – Type D personality is a vulnerabilitycharacteristic related to cardiovascular morbidity and mortality (Steptoe and Molloy, 2007). The TypeD personality is distinct from other psychological characteristics that may predict prognosis in heartdisease, such as social isolation of depression (Kupper and Denollet, 2007). Several methods ofassessing Type D personality have been developed.

A long-term study over eight decades has found that conscientiousness in both childhood andadulthood is associated with longevity, partly because high levels of conscientiousness are related tolow levels of risk behaviour including cigarette smoking, poor diet and activity levels, excessive use ofalcohol or drugs, violence, risky sexual behaviour, risky driving and suicide (Bogg and Roberts, 2004)

Psychological hardiness and resilianceThere is evidence that certain personality constellations may be associated with positive healthoutcomes. Kobasa introduced the notion of psychological hardiness made up of three characteristics:sense of control, commitment, and the viewing of change as exciting challenge rather than threat. Arelated concept is psychological resilience, the ability to bounce back from negative events by usingpositive emotions to cope.

The role of personality characteristics in predisposing patients to CHD is an evolving field of study.There are implications for psychotherapeutic interventions with CHD patients and their families.

References



Bogg, T., and Roberts, B.W., 2004, Conscientiousness and health-related behaviors: a meta-analysis ofthe leading behavioural contributors to disease. Psychological Bulletin; 130: 887-919.

Kupper, N. and Denollet, J., 2007, Type D personality as a prognostic factor in heart disease:assessment and mediating mechanisms. Journal of Personality Assessment; 89(3): 265-276.

Myrtek, M., 2001, Meta-analyses of prospective studies on coronary heart disease, type A personality,and hostility. International Journal of Cardiology; 79(2-3): 245-251.

Steptoe, A. and Molloy, G.J. 2007, Personality and heart disease. Editorial. Heart; 93(7): 783-784; seealso other articles in this edition.



Alder, B., 2004, Psychology and sociology applied to medicine : an illustrated colour text, 2nd ed.,Churchill Livingstone, Edinburgh ; London ; New York

Stevens, V.M., 2007, Behavioral science, 2nd ed., Mosby/Elsevier, Philadelphia

These text books provide a brief introduction to the main approaches to personality and personalitymeasurement. For those unfamiliar with the topic it can provide a quick overview.

For further information, the following has additional value.


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Alder, B., 2004, Psychology and sociology applied to medicine : an illustrated colour text, 2nd ed.,Churchill Livingstone, Edinburgh ; London ; New York

Stevens, V.M., 2007, Behavioral science, 2nd ed., Mosby/Elsevier, Philadelphia

These text books provide a brief introduction to the main approaches to personality and personalitymeasurement. For those unfamiliar with the topic it can provide a quick overview.

For further information, the following has additional value.

Friedman, H.S., 2008, The multiple linkages of personality and disease. Brain, Behavior, andImmunity; 22: 668-675.


LEARNING TOPIC - Pregnancy and cardiovascular system

Pregnancy is associated with a marked change in cardiovascular function of the mother which isaimed at ensuring that the fetus is well served with nutrients, the mother can adequately dispose ofwaste products from her own increased metabolism and that of the fetus, the breasts can bedeveloped for breast feeding, and the mother can be protected from blood loss at the time of delivery.The changes in the cardiovascular system

occur early in pregnancy and proceed the fetal demandexceed fetal demandare all completely reversed after delivery

The changes that involve the cardiovascular system specifically are

the formation of a low resistance vascular network in the uterus which contains approximately 1litre of blood at termprogesterone induced vasodilatation in the body causing a marked increase in regional bloodflow

kidney flow increases by 60% to improve excretionskin flow increases by 50% to improve heat lossliver flow increases by 50% to improve hepatic functionincrease in gut flow improves nutrient absorptionincrease in blood flow to the breast is approximately 200% over non pregnant levels toensure that the breasts are developed ready for feeding the infant.uterine flow increases from 30mls/min in the non-pregnant woman to 600mls/min at term7the only organ not to have increased blood flow is the brain

Women are prone to fainting in pregnancy due to low BP caused by the vasodilatation associated withprogesterone. The maximum of vasodilatation occurs in the middle trimester and blood pressure islowest at that time.

Plasma volume increases by 40%. This increase is related to fetus size and is induced byincreased Aldosterone which results from increased renin excretion both at the kidney anduterus.Red cell mass increases by 18-20%. This increase is smaller than that of the plasma volume anda physiological anaemia therefore results with the normal haemoglobin level being between a105-140 grams/litre at term.The vasodilatation due to the progesterone and the large uterine blood flow could potentiallycause a massive fall in blood pressure. This, however, does not occur due to the increase inblood volume as outlined above and because cardiac output is increased. Cardiac outputincreases mainly because of an increase in the heart rate. There is also a small increase instroke volume. This increase in cardiac output is sufficient to ensure good supplies of oxygendelivered to the fetus and other tissues in the body. The increases in plasma volume, heart rateand stroke volume result in a decrease in cardiac reserve (the ability to increase cardiac outputabove the normal level). This means that pregnant women are prone to congestive heart failureif they have an abnomal heart or if they are treated with drugs or fluids that speed up the heartrate, drop the blood pressure, or increase circulating volume.The increase in the uterine size causes an upward pressure on the diaphragm. This upwardpressure on the diaphragm causes a change in the cardiac axis in the electrocardiogram, withthe axis being rotated to the right as compared to the non-pregnant woman.


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cause a massive fall in blood pressure. This, however, does not occur due to the increase inblood volume as outlined above and because cardiac output is increased. Cardiac outputincreases mainly because of an increase in the heart rate. There is also a small increase instroke volume. This increase in cardiac output is sufficient to ensure good supplies of oxygendelivered to the fetus and other tissues in the body. The increases in plasma volume, heart rateand stroke volume result in a decrease in cardiac reserve (the ability to increase cardiac outputabove the normal level). This means that pregnant women are prone to congestive heart failureif they have an abnomal heart or if they are treated with drugs or fluids that speed up the heartrate, drop the blood pressure, or increase circulating volume.The increase in the uterine size causes an upward pressure on the diaphragm. This upwardpressure on the diaphragm causes a change in the cardiac axis in the electrocardiogram, withthe axis being rotated to the right as compared to the non-pregnant woman.The jugular venous pressure (a measure of pressure to the right side of the heart) is increasedin pregnancy due to the increased intravascular volume. The jugular venous pressure istherefore raised in pregnancy and is an unreliable measure of right sided heart pressures inwomen from 20 weeks of pregnancy onwards.

References



Fetal cardiovascular physiology, in, Creasy, R.K., Resnik, R., Iams, J.D.,(eds.), 2004, Maternal-fetalmedicine : principles and practice, 5th edn., W.B. Saunders Co., Philadelphia.

Author: Dr Henry Murray, Obstetrics and Gynaecology

LEARNING TOPIC - Prenatal Diagnosis and Down Syndrome

The population frequency of Down Syndrome is approximately one in six hundred and sixty in NSW.

During the 1950s several epidemiologic studies of Down syndrome showed a strong correlation inincidence of Down syndrome and maternal age. The incidence of Down syndrome rising from one infour hundred and seventy four at maternal age 20-24 to one in twenty eight at maternal age 45 (Seefact sheets 15 and 27 at http://www.genetics.com.au/factsheet/default.htm).

This observation became the cornerstone of interventions requested by couples to reduce the risk ofhaving a baby with Down syndrome.

Fetal Diagnosis of Chromosome AnomaliesFetal diagnosis of chromosome aneuploidy, specifically Down syndrome became feasible in the early1970s when it became technically feasible to karyotype dividing fetal cells from amniotic fluid. Othertechnical advances permitted highly accurate diagnosis from analyses of chorionic villus cells. Initiallyfetal diagnosis was offered where the risk of Down syndrome approximated the risk of the procedure(procedure related pregnancy loss of 1 %).

Fetal Screening for Chromosome AnomaliesFetal screening which at best provides a risk estimate is based on combinations of:

Maternal serum parameters of fetal well-being (e.g. Alpha Fetoprotein, Unconjugated Estriol,Human Chorionic Gonadotrophin, Inhibin A)Fetal measurement (e.g. nuchal fold translucency, femoral length, length of nasal spine).

Considerations to be taken into account in counselling families and also evaluating the public healthefficacy of screening interventions include:

the sensitivity, specificity, risks and negative consequences associated with the variousscreening methods (e.g. Triple test, Nuchal Fold Translucency) that are available forprenatal prediction of Down syndrome;the need for and benefits of genetic counselling and informed consent to screening ordiagnostic testing;the dilemmas encountered by prospective parents faced with the possibility of the birthand subsequent parenting and care of a child with Down syndrome; and how factors suchas the prospective mother’s age, whether the prospective parents already have childrenand whether they already have a child with Down syndrome affect the dilemmas;the legal and ethical issues associated with decisions about the abortion of a fetus withDown syndrome.

References


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prenatal prediction of Down syndrome;the need for and benefits of genetic counselling and informed consent to screening ordiagnostic testing;the dilemmas encountered by prospective parents faced with the possibility of the birthand subsequent parenting and care of a child with Down syndrome; and how factors suchas the prospective mother’s age, whether the prospective parents already have childrenand whether they already have a child with Down syndrome affect the dilemmas;the legal and ethical issues associated with decisions about the abortion of a fetus withDown syndrome.

References



Patterson D, Costa AC. Down syndrome and genetics - a case of linked histories. Nature ReviewsGenetics 2005 Feb;6(2):137-47.

Marteau TM, Croyle RT. Psychological responses to genetic testing . BMJ 1998; 316(7132):693-6.

New South Wales Genetic Services Advisory Committee. Prenatal Testing/Screening for DownSyndrome & Other Chromosomal Abnormalities Website

Gibert RE, Augood C, Ades AE et al. Screening for Down's syndrome: effects, safety, and costeffectiveness of first and second trimester strategies . BMJ 2001; 323(7310):423-426.

Hall S, Bobrow M, Marteau TM. Psychological consequences for parents of false negative results onprenatal screening for Down's syndrome: retrospective interview study . BMJ 2000;320(7232):407-412.

Wellesley D, Boyle T, Barber J, Howe DT. Retrospective audit of different antenatal screening policiesfor Down syndrome in eight district general hospital in one health region. BMJ2002; 325(7354):15-18.

Raeburn S. Evidence based screening for Down syndrome . BMJ 2000; 320(7235):592-593.

Howe DT, Gornall R, Wellesley D, Boyle T, Barber J. Six year survey of screening for Down syndromeby maternal age and mid-trimester ultrasound scans . BMJ 2000; 320(7235):606-610.


LEARNING TOPIC - Regulation of cerebral blood flow

The cerebral blood flow remains relatively constant over a wide range of perfusion pressure. Thisappears to be a consequence primarily of a tight coupling between neural (metabolic) activity and theresistance of cerebral blood vessels.

The brain relies almost exclusively on glucose as its substrate for energy metabolism. Therefore,because it is unable to store energy, the brain requires a constant supply of oxygenated bloodcontaining an adequate concentration of glucose. In humans at rest the cerebral blood flow is 15-20%of the total cardiac output, and the oxygen consumption of the brain is about 20% of the oxygenconsumption for the whole body.

Anatomical features of the cerebral circulationThere is a high degree of collateralization of cerebral arteries. In particular, there is considerablecommunication between the basal cerebral arteries at the circle of Willis, between the branches of theexternal carotid artery and the intracerebral circulation, and between cerebral arteries on the surfaceof the brain. This collateralization reduced the risk that occlusion of one artery will lead to inadequateblood flow (ischaemia) to the brain region normally supplied by that artery, because in that situationcollateral vessels can supply adequate blood flow. There are, however, regions of the brain that aresupplied by arteries which do not communicate with other arteries, and such regions regions aretherefore more vulnerable to ischaemic damage in the event of occlusion of the arteries that supplythem.

Autoregulation of cerebral blood flowAs in any region, the blood flow to the brain (cerebral blood flow, CBF) depends upon the perfusionpressure (i.e. the difference between the pressure in the cerebral arteries and the cerebral veins) andthe vascular resistance in the brain (cerebrovascular resistance). The mean pressure in the cerebralarteries is essentially the same as in all systemic arteries (i.e. the mean arterial pressure), while thecerebral venous pressure is usually low (~ 10 mmHg or less). Thus, the perfusion pressure dependsprimarily on the systemic arterial pressure. The cerebrovascular resistance depends mainly on the


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collateral vessels can supply adequate blood flow. There are, however, regions of the brain that aresupplied by arteries which do not communicate with other arteries, and such regions regions aretherefore more vulnerable to ischaemic damage in the event of occlusion of the arteries that supplythem.

Autoregulation of cerebral blood flowAs in any region, the blood flow to the brain (cerebral blood flow, CBF) depends upon the perfusionpressure (i.e. the difference between the pressure in the cerebral arteries and the cerebral veins) andthe vascular resistance in the brain (cerebrovascular resistance). The mean pressure in the cerebralarteries is essentially the same as in all systemic arteries (i.e. the mean arterial pressure), while thecerebral venous pressure is usually low (~ 10 mmHg or less). Thus, the perfusion pressure dependsprimarily on the systemic arterial pressure. The cerebrovascular resistance depends mainly on theinternal diameters of the small intracranial arteries and arterioles, which are the main resistancevessels. This is described by the following equation:CBF = cerebral perfusion pressure/cerebrovascular resistance.

A remarkable feature of the cerebral circulation is the fact that the CBF remains relatively constantover a wide range of mean arterial pressure (approximately 60-150 mmHg). This implies that, withinthis pressure range, a decrease in arterial pressure is accompanied by a decrease in cerebrovascularresistance (i.e. vasodilation), while an increase in arterial pressure is accompanied by an increase incerebrovascular resistance (i.e. vasoconstriction). The effect of this is to ensure that within this rangeof arterial pressure the CBF is appropriate for the metabolic demands of the brain. When the arterialpressure decreases below the lower limit of cerebral autoregulation, the CBF falls significantly, butthis is partly compensated for by an increase in oxygen extraction. Once this compensatory increasein oxygen extraction has reached its limit, however, a further decrease in arterial pressure will lead toischaemia. For example, an acute and precipitous decrease in arterial pressure that occurs during thevaso-vagal response may cause transient ischaemia of the cerebral cortex and loss of consciousness(syncope). Conversely, when the arterial pressure increases above the upper limit of cerebralautoregulation, oedema may occur.

The upper and lower limits of autoregulation are increased in people with chronic hypertension. Whilethis has a protective effect when arterial pressure is elevated, a decrease in arterial pressure inhypertensive patients can result in brain ischaemia at levels of pressure which, in normotenivepeople, would not be associated with ischaemia. In addition, the upper and lower limits ofautoregulation are also increased as a result of stimulation of sympathetic nerves supplying thecerebral blood vessels. Thus, in conditions where sympathetic activity increases acutely (e.g. duringexercise or stress) the increase in the autoregulatory range tends to match the acute increase inarterial pressure that occurs under these conditions.

Factors controlling cerebrovascular resistanceAlthough cerebral blood vessels are innervated by sympathetic nerves, their function appears to beprimarily to vary the autoregulatory range, as discussed above. The main factor regulating theresistance of cerebral arterioles is local metabolic activity. An increase in the neuronal activity in aparticular brain region leads to an increase in the production of metabolites such as H+ ions oradenosine. This in turn results in vasodilation in that region. It is possible that nitric oxide (NO) alsoplays a key role, mediating the vasodilation that is triggered by the increased concentration ofmetabolites. It is likely that this tight coupling between changes in metabolic activity andcerebrovascular resistance is the principal mechanism underlying cerebral autoregulation. Forexample, a decrease in arterial pressure would initially cause a reduction in cerebral blood flow,leading to a mismatch between the rate of production of metabolites and their removal, so that anincrease in the concentration of metabolites would occur, leading to vasodilation which in turn wouldrestore CBF, despite the reduction in arterial pressure.

The CBF is also very sensitive to changes in the concentration of CO 2 in the arterial blood. This is

largely mediated via the resultant changes in the concentration of H+ ions in the extracellular fluidsurrounding cerebral arterioles, but may also in part be mediated indirectly, via pH-dependent releaseof other vasoactive factors, such as prostaglandins or NO. One potential serious consequence of thesensitivity of CBF to changes in blood CO

2 levels is that hyperventilation can result in a large

decrease in CBF, even leading to unconsciousness. This is explained by the fact that hyperventilationvan greatly reduce the blood CO

2 level, resulting in cerebral vasoconstriction and hence reduced CBF.

Recent studies have also indicated that glial cells (astrocytes) in the brain also may play an importantrole in the coupling between neuronal activity (metabolic activity) and CBF. According to this

hypothesis, neurotransmitters released by neurons cause a change in the intracellular Ca 2+

concentration of nearby astrocytes, which then in turn release vasodilating compounds (e.g.prostaglandins). Consistent with this hypothesis, astrocytic processes are closely associated withboth synapses and cerebral blood vessels. Further studies are required, however, before theimportance of this neuron-astrocyte-blood vessel pathway in the regulation of CBF can be fullyevaluated.

References


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Recent studies have also indicated that glial cells (astrocytes) in the brain also may play an importantrole in the coupling between neuronal activity (metabolic activity) and CBF. According to this

hypothesis, neurotransmitters released by neurons cause a change in the intracellular Ca 2+

concentration of nearby astrocytes, which then in turn release vasodilating compounds (e.g.prostaglandins). Consistent with this hypothesis, astrocytic processes are closely associated withboth synapses and cerebral blood vessels. Further studies are required, however, before theimportance of this neuron-astrocyte-blood vessel pathway in the regulation of CBF can be fullyevaluated.

References



Markus, H.S. Cerebral perfusion and stroke . Journal of Neurology, Neurosurgery and Psychiatry.2004, March, 75: 353-361.

For those interested in current ideas ideas the role of astrocytes in regulating CBF, see:

Anderson, C.M. and Nedergaard, M. Astrocyte-mediated control of cerebral microcirculation . Trendsin Neurosciences 2003, 26(7): 340-345.


LEARNING TOPIC - Short term regulation of blood pressure

Disturbances in arterial blood pressure that occur over the short term (seconds or minutes) arecompensated for by rapidly-acting control systems, of which the single most important is the arterialbaroreceptor reflex.

Arterial pressure is regulated by several interrelated systems, which have different time-courses ofaction. These can be divided into short-term, intermediate term and long-term mechanisms. Theshort-term mechanisms are neural reflexes, the intermediate mechanisms are hormonal, and thelong-term mechanisms consists mainly of the renal system which relates blood volume and hencearterial pressure. This learning topic will focus on the short-term mechanisms.

Arterial baroreceptor reflexIn the short term (ie seconds or minutes), the main mechanism regulating blood pressure is thearterial baroreceptor reflex. The arterial baroreceptors are spray-type nerve endings lying in the wallsof the carotid sinus and aortic arch. They are stretch receptors, but signal pressure by responding tochanges in the pressure-induced stretch of the arterial wall. The primary afferent fibres originatingfrom the carotid sinus and aortic arch baroreceptors (which run in the glossopharyngeal and vagalcranial nerves, respectively) terminate in the nucleus of the solitary tract (NTS), within the medullaoblongata. From the NTS, baroreceptor afferent signals are transmitted over central pathways to thevagal preganglionic neurons (located in the medulla oblongata) and sympathetic preganglionicneurons (in the thoracic and upper lumbar segments of the spinal cord) that regulate thecardiovascular system.

The baroreceptors are tonically active at normal levels of arterial pressure, and are able to signalchanges in pressure within the range from approximately 50 mmHg (threshold) to 160 mmHg(saturation level). A change in the firing rate of baroreceptors, in response to a change in pressure,reflexly alters the activity of sympathetic nerves innervating the heart and blood vessels, and vagalnerves innervating the heart, via the central pathways referred to above. In this way, a transientchange in arterial pressure (eg as a consequence of a change in posture) is rapidly compensated for,so that the arterial pressure is restored back close to its previous level.

The baroreceptor control system is of little or no importance in long-term regulation of arterialpressure, simply because the baroreceptors adapt (within 1-2 days) to whatever pressure level theyare exposed to. Thus, dysfunction of the baroreceptor reflex cannot be the cause of maintained higharterial pressure (hypertension). Instead, the main importance of the baroreceptor reflex is inbuffering disturbances to the cardiovascular system, as may arise from changes in posture, metabolicactivity or external threats triggering sympathetic reactions.

Short-term control of arterial pressure by other reflexesApart from the baroreceptors, other groups of receptors can also reflexly alter the activity ofautonomic nerves innervating the cardiovascular system. These include the arterial chemoreceptors(located in the carotid body and aortic arch) and receptors in the low-pressure part of the circulation(particularly the left and right atria). Primary afferent fibres originating from these receptors, like thearterial baroreceptors, run in the glossopharyngeal or vagal nerves and terminate in the NTS.


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are exposed to. Thus, dysfunction of the baroreceptor reflex cannot be the cause of maintained higharterial pressure (hypertension). Instead, the main importance of the baroreceptor reflex is inbuffering disturbances to the cardiovascular system, as may arise from changes in posture, metabolicactivity or external threats triggering sympathetic reactions.

Short-term control of arterial pressure by other reflexesApart from the baroreceptors, other groups of receptors can also reflexly alter the activity ofautonomic nerves innervating the cardiovascular system. These include the arterial chemoreceptors(located in the carotid body and aortic arch) and receptors in the low-pressure part of the circulation(particularly the left and right atria). Primary afferent fibres originating from these receptors, like thearterial baroreceptors, run in the glossopharyngeal or vagal nerves and terminate in the NTS.

The arterial chemoreceptors are stimulated primarily by a decrease in the pO 2 level of the arterial

blood, but can also be stimulated by a large fall in arterial pressure, as may occur during severehaemorrhage. Stimulation of the chemoreceptors results in a reflex vasoconstriction, which helps toraise arterial pressure. Receptors in the atria respond primarily to changes in blood volume, whichaffects the pressure within the atria and central veins. A decrease in atrial pressure (eg as aconsequence of a haemorrhage) results in a reflex increase in the activity of sympathetic vasomotornerves, particularly those innervating the kidney. In addition, signals from atrial receptors also reachthe hypothalamus and cause an increase in the release of antidiuretic hormone (vasopressin) fromthe pituitary gland. In summary, then, a decrease in atrial pressure triggers reflex sympathetic andhormonal changes that increase vascular resistance and reduce urine production. Conversely, anincrease in atrial pressure has the opposite effect, producing a reflex vasodilatation and rise in urineproduction. The atrial reflex plays an important role in the cardiovascular adjustments to a change inposture, and to haemorrhage.

References



Guyton, A. C. and J. E. Hall, 2006, Textbook of medical physiology, 11th ed., Elsevier Saunders,Philadelphia. Chapter 18 (Nervous Regulation of the Circulation, and Rapid Control of Arterial Pressure)

For more specialised reading, the following are useful references:

Agewall S et al. Reflexogenic neuronal and humoral responses to selective stimulation of low-pressurecardiopulmonary receptors in man. J. Intern. Med. 1991; 229(2): 151-158.

Coleridge HM, Coleridge JCG. Cardiovascular afferents involved in regulation of peripheral vessels .Annu. Rev. Physiol 1980; 42(1): 413-427.

Hainsworth R. Reflexes from the heart . Physiol. Rev. 1991; 71(3): 617-658.


LEARNING TOPIC - Social roles: responses to health and illness

Role theory is a sociological approach which conceives of most social situations having characteristicbehaviour patterns or roles. When individuals are placed in certain social positions, there areexpectations of their own behaviours and those of others with whom they are interacting. People playmany roles in their lives; roles are learned, culturally-related and sometimes influenced by gender.The role of the doctor involves performing actions, having aims, addressing problems and interactingwith others (patients, patients’ families, other health professionals) in ways which are relativelycommon to all doctors. By abstracting the common features of the role it is possible to clarifyinteractions and purposes and gain insight and understanding of various roles in the health caresystem.

The Sick RoleA person with an illness has a relatively well defined role in most societies, as being sick is associatedwith a set of obligations and responsibilities which were first described by sociologist Talcott Parsons(1951). The four main expectations for the sick role are: (a) a right to exemption from normal socialrole responsibilities, eg work; (b) a right not to be held accountable for the illness; (c) a duty toexperience illness as undesirable and not to resign themselves to the illness; (d) a duty to seek outexpert assistance and to cooperate with recommended treatment in attempting to get well. Medicalpractitioners are empowered to allow patients to enter this role, and as such, become socialregulators. One implication of the sick role is that some illnesses are viewed as legitimate, and otherswhich might be interpreted as being the 'fault' of the patient (such as substance abuse related


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system.

The Sick RoleA person with an illness has a relatively well defined role in most societies, as being sick is associatedwith a set of obligations and responsibilities which were first described by sociologist Talcott Parsons(1951). The four main expectations for the sick role are: (a) a right to exemption from normal socialrole responsibilities, eg work; (b) a right not to be held accountable for the illness; (c) a duty toexperience illness as undesirable and not to resign themselves to the illness; (d) a duty to seek outexpert assistance and to cooperate with recommended treatment in attempting to get well. Medicalpractitioners are empowered to allow patients to enter this role, and as such, become socialregulators. One implication of the sick role is that some illnesses are viewed as legitimate, and otherswhich might be interpreted as being the 'fault' of the patient (such as substance abuse relatedillnesses), are viewed as illegitimate. Conversely, some illness sufferers push to have their illnessrecognised as a medical condition, this medicalisation supposedly changing society's view of thesufferer from 'bad' to 'ill' (as has happened in the past with mental illness). Parson's sick role hasbeen criticised as: (1) more appropriate to acute disorders, not chronic illness where the patient mayin fact be encouraged to continue normal social role obligations; (2) medicalising some disorders andremoving patient's responsibilities for behavioural choices; and (3) culture- and class-related.

LabellingFriedson (1970) comments on the unequal nature of the doctor-patient relationship, and the power ofthe doctor to label illness. The process of labelling is two-pronged; on one hand it may assist thepatient by allowing understanding of their condition and relief from social role obligations, whereason the other hand it may cause the patient to enter the sick role unnecessarily (eg male patients whodefined themselves as sick, when it was found that they had asymptomatic high blood pressure), andmay stigmatise the patient (as with mental illness).

Illness BehaviourMechanic introduced the term 'illness behaviour' to describe activities undertaken by a person whohas symptoms in order to define the state of their health and discover a suitable remedy. Associatedwith this is the premise that the experience of illness may be used to achieve social and personalgoals unrelated to alterations in biological systems or the pathogenesis of disease, that is, secondarygain. Particular groups of individuals have been found to be under-utilisers of medical services and tobe more likely to tolerate symptoms of disease, have a different definition of symptoms from themedical profession, be likely to consult friends or family or alternative healers, be frightened or waryabout going to the doctor, feel that little could be done about their condition and be unable to 'maketime' to go to the doctor. These intervening variables mediating between the presence of symptomsand the act of consulting a doctor are often patterned according to social and cultural factors,including the ability to tolerate pain, the social and cultural meaning of symptoms, and the socialnetwork of the individual.

Abnormal Illness BehaviourIn Mechanic's formulation of illness behaviour, the term 'abnormal illness behaviour' isnon-evaluative and describes no more than statistical variation from a norm. Pilowsky, however, hasdeveloped an extension of this usage to cover a range of disease-associated behaviours often labelledhypochondriacal, hysterical, malingering, and so on. He defines abnormal illness behaviour as 'thepersistence of an inappropriate or maladaptive mode of perceiving, evaluating and acting in relationto one's own state of health, despite the fact that a doctor (or other appropriate social agent) hasoffered a reasonably lucid explanation of the nature of the illness and the appropriate course ofmanagement to be followed'. A number of contemporary issues now mean that illness behaviours arecurrently important to governments, the medical profession and the wider community. These issuesinclude the rising number of people with chronic illness, widening definitions of health and illness,re-thinking acceptable quality of life, wider use of services, the increasing availability and use ofalternative and complementary therapies, easier public access to information on illness andtreatment, and greater emphasis on patient empowerment and involvement in decision making.

References



Broome, A. and S. P. Llewelyn, 1995, Health psychology : process and applications, 2nd ed., Chapman& Hall, Melbourne.

George, J. and A. Davis, 1998, States of health : health and illness in Australia, 3rd ed., AddisonWesley Longman, Melbourne.

Pilowsky, I., 1997, Abnormal illness behaviour. Wiley.

Rogers, T., 2001. Barriers to the doctor as patient role: a cultural construct. Royal Australian Collegeof General Practitioners.http://www.racgp.org.au/gphealth/doctorsaspatients


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Available in Medical Library: see Library Catalogue

Broome, A. and S. P. Llewelyn, 1995, Health psychology : process and applications, 2nd ed., Chapman& Hall, Melbourne.

George, J. and A. Davis, 1998, States of health : health and illness in Australia, 3rd ed., AddisonWesley Longman, Melbourne.

Pilowsky, I., 1997, Abnormal illness behaviour. Wiley.

Rogers, T., 2001. Barriers to the doctor as patient role: a cultural construct. Royal Australian Collegeof General Practitioners.http://www.racgp.org.au/gphealth/doctorsaspatients


LEARNING TOPIC - Structure of heart and great vessels

Structure of the pericardium and heart

Revise the structure and relationships of the pericardium.How is the external surface of the heart described?What are the major structures and their locations within the four chambers of the heart?Review briefly the organisation of the conducting system of the heart.

Surface anatomy of the heart

How is the middle mediastinum defined?What are the surface markings of the heart and its valves as projected onto the anterior chestwall?What components of the heart make up the four borders of the heart when it is viewed fromanteriorly?

The great vessels

Briefly review the position, relationships and branches or tributaries of the aorta, superior andinferior vena cava and the pulmonary arteries and veins. In particular note their connectionswith the heart and their relationships as they leave or enter the heart.

References

Resources material associated with this Learning Topic.

Moore, K. L., et al., 2006, Clinically oriented anatomy, 5th ed., Lippincott Williams & Wilkins,Baltimore, MD. Chapter 3 (Pelvis and Perineum)

Drake, R. L., et al., 2005, Gray's anatomy for students, ed., Elsevier/Churchill Livingstone,Philadelphia. Chapter 3 (Thorax)

Ross, M. H. and W. Pawlina, 2006, Histology : a text and atlas with correlated cell and molecularbiology, 5th ed., Lippincott Wiliams & Wilkins, Baltimore, MD. Chapter 13 (Cardiovascular system)

Author: Dr Richard Ward, Anatomy and Histology

LEARNING TOPIC - Support for carers

A carer is someone who provides care and support for a parent, partner, child, relative or friend whohas a disability, is frail and aged, or who has a chronic mental or physical illness. It is a fact that manyof us will provide and/or receive such care at some stage during our lives.

Down syndrome is one of many conditions where an individual may be, or may become, reliant upontheir partners, family members or other people to provide continuing care at home. Other examples ofconditions where care may also be required include people with HIV, arthritis, cancer, cardiac disease,cerebral palsy, dementia, diabetes, emphysema and other respiratory conditions, head injury, otherintellectual disabilities, mental illness, motor neurone disease, multiple sclerosis, muscular dystrophy,Parkinson's disease, spinal cord injury and stroke, as well as frail aged people and people receiving


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A carer is someone who provides care and support for a parent, partner, child, relative or friend whohas a disability, is frail and aged, or who has a chronic mental or physical illness. It is a fact that manyof us will provide and/or receive such care at some stage during our lives.

Down syndrome is one of many conditions where an individual may be, or may become, reliant upontheir partners, family members or other people to provide continuing care at home. Other examples ofconditions where care may also be required include people with HIV, arthritis, cancer, cardiac disease,cerebral palsy, dementia, diabetes, emphysema and other respiratory conditions, head injury, otherintellectual disabilities, mental illness, motor neurone disease, multiple sclerosis, muscular dystrophy,Parkinson's disease, spinal cord injury and stroke, as well as frail aged people and people receivingpalliative care at home at the end of life.

Increasing awareness has been given in recent years to the provision of support and assistance forcarers. Many families have found that they have had to provide homecare for family members withsignificant disability particularly since the closure of residential facilities for people with intellectualdisability and the lack of availability of suitable institutional care for people with many chronicconditions. There is no doubt that many people with chronic conditions and their families preferhomecare however there are many challenges.

One of the important roles of the doctor providing medical care for a person with a chronic conditionis to ensure that the well being of their carers is also being addressed. After all if the carers areunable to cope, then the care of the individual may be in jeopardy. The needs of all family membersshould be addressed; this is particularly important for other children, in the case of a child with adisability, and for the primary care giver in any situation. Often, but not always, the burden of carefalls upon the women in the family. It is important that the family and other carers are involved inmedical discussions and decision making, with the consent of the individual patient. It is important toask carers about how they are coping and to pick up early signs of stress and to provide assistanceand support.

Home visits are an essential component of Australian general practice. This is particularly the case forpeople with chronic disabling conditions or the terminally ill. Seeing the person in their homeenvironment can help uncover concerns and allow the doctor to more clearly appreciate some of thedifficulties which face carers. A wise family doctor will listen to concerns expressed by carers. After allthe carers are looking after the individual 24 hours a day and have the opportunity to observe anddetect problems early on.

Support networks are important. These may exist both within the family and from outside and mayinclude the family's general practitioner and visiting nursing professionals. Such networks canengender security and assist in alleviating or preventing stressful circumstances.

It is important that carers are aware of available support services. The Carers Australia providesinformation, education, counselling, advocacy and other ongoing supports for carers throughbranches in all states and territories of Australia. This can be a useful first point of contact for carersand clinicians looking for suitable resources. See: www.carersaustralia.com.au The website alsoinclude resources including information for carers on financial support and pensions, guidelines onhow to provide safe care at home, advice on looking after yourself and respite care. It is available in13 languages.

References



Students can find additional useful background material on the role of carers of people with chronicillness in Australia from the following references:

Bridges-Webb C, Giles B, Speechly C, Zurynski Y, Hiramanek N. Patients with dementia and theircarers in general practice. Australian Family Physician 2006;35:923-4. www.racgp.org.au/afp/200611/12571

Brodaty H, Green A. Who cares for the carer? The often forgotten patient. Australian Family Physician2002, 31(9):833-836.

Bulsara CE, Fynn N. An exploratory study of GP awareness of carer emotional needs in WesternAustralia. BMC Family Practice 2006, May, 7:33.

Students can find additional information on support for carers in Australia from the followingorganisations:

Carers Australia www.carersaustralia.com.au

NSW Council for Intellectual Disability. www.nswcid.org.au/


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2002, 31(9):833-836.

Bulsara CE, Fynn N. An exploratory study of GP awareness of carer emotional needs in WesternAustralia. BMC Family Practice 2006, May, 7:33.

Students can find additional information on support for carers in Australia from the followingorganisations:

Carers Australia www.carersaustralia.com.au

NSW Council for Intellectual Disability. www.nswcid.org.au/

Author: Professor Simon Willcock, General Practice

LEARNING TOPIC - Syncope

Syncope (or fainting) is triggered by an abrupt decrease in arterial blood pressure, which in turn mayresult from a variety of causes. The most common cause (vasovagal syndrome) is associated withchanges in sympathetic and cardiac vagal activity.

DefinitionSyncope is defined as a disturbance or loss of consciousness as a result of an abrupt reduction ofblood flow to the brain, which is typically of short duration (seconds to minutes).

Causes of syncopeNormally, blood flow to the brain is regulated by an intrinsic autoregulatory mechanism, whichmaintains blood flow at a level sufficient to meet the metabolic demands of the brain, even if thereare transient decreases in mean arterial blood pressure. However, if there is a large fall in meanarterial pressure (i.e. to a level < 45-50 mmHg), the autoregulatory mechanism is insufficient tomaintain a level of cerebral blood flow that is sufficient to meet the metabolic demands of the brain,resulting in a loss of consciousness.

Arterial blood pressure is normally regulated by the baroreceptor reflex, so that a large decrease inblood pressure (hypotension) can only occur if the factor causing the hypotension is so great that itcannot be compensated for by the baroreceptor reflex, or if the baroreceptor reflex itself is impaired.

There are four main factors that can cause abrupt and large decreases in blood pressure, leading tosyncope:

Obstruction to the circulation. Any factor which obstructs the outflow from the left or rightventricles, or which impairs the pumping capacity of the ventricles, may cause a fall in cardiacoutput which, if severe enough, will lead to a large fall in arterial pressure. Such factors includeaortic stenosis (which narrows the aorta), hypertrophic cardiomyopathy (in which thecontractility of the cardiac muscle is impaired), pulmonary stenosis (which narrows thepulmonary artery), or pulmonary embolism (in which the outflow resistance of the rightventricle is greatly increased).Transient arrhythmias. A rapid increase in the rate of ventricular contractions (ventriculartachycardia) may result in a very short filling time and hence greatly reduced stroke volume,leading to a reduced cardiac output despite the increased heart rate. The ventricular tachycardiamay occur as a result of abnormalities of the cardiac pacemaker (sino-atrial node) or in theconduction of action potentials through the heart. Conversely, other abnormalities of thepacemaker or cardiac conduction pathways may lead to a slowing of the heart rate(bradycardia), which if severe enough will also lead to a greatly reduced cardiac output. Thedecrease in cardiac output in turn will result in a decrease in arterial blood pressure.Neurological disorders . A variety of neurological disorders can result in dysfunction of the vagalparasympathetic nerves innervating the heart, or sympathetic vasoconstrictor nervesinnervating the blood vessels, leading to an impairment of the normal baroreceptor reflexcontrol of blood pressure. A feature of these conditions is a reduction in blood pressure whenthe subjects stand up (postural hypotension).Vasovagal syndrome. This is the most common cause of syncope, and is so named because it ischaracterised by a combination of vagally mediated cardiac slowing (bradycardia) andperipheral vasodilation. The result is that both cardiac output and total peripheral resistance isreduced, so that arterial pressure falls sharply, to the point where transient cerebral ischaemiaand loss of consciousness occurs. It is the vasodilation that is the most important factor,because blockade of the vagally-mediated bradycardia (by injection of atropine) does notprevent the syncope. Attacks are usually initiated by emotional stimuli (e.g. fainting at the sightof blood, or on receiving very bad news). Vasovagal syncope occurs infrequently in healthypeople, but in some people occurs frequently and in the absence of any obvious stimulus - inthese cases the term 'malignant vasovagal syndrome' is used.

Studies in humans have demonstrated that the vasodilation associated with vasovagal syncope is due


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Vasovagal syndrome. This is the most common cause of syncope, and is so named because it ischaracterised by a combination of vagally mediated cardiac slowing (bradycardia) andperipheral vasodilation. The result is that both cardiac output and total peripheral resistance isreduced, so that arterial pressure falls sharply, to the point where transient cerebral ischaemiaand loss of consciousness occurs. It is the vasodilation that is the most important factor,because blockade of the vagally-mediated bradycardia (by injection of atropine) does notprevent the syncope. Attacks are usually initiated by emotional stimuli (e.g. fainting at the sightof blood, or on receiving very bad news). Vasovagal syncope occurs infrequently in healthypeople, but in some people occurs frequently and in the absence of any obvious stimulus - inthese cases the term 'malignant vasovagal syndrome' is used.

Studies in humans have demonstrated that the vasodilation associated with vasovagal syncope is dueto an inhibition (usually complete abolition) of sympathetic vasoconstrictor nerve activity. Thisfinding indicates that the baroreceptor reflex is suppressed during a vasovagal attack, because thefall in arterial pressure would normally trigger a reflex increase in sympathetic vasoconstrictoractivity. It is thought that the sympathoinhibition and cardiac vagal activation is a stereotypedautonomic response, triggered by centers in the forebrain that receive inputs activated by emotionalstimuli. The survival value of the vasovagal syncope is unclear; it is conceivable, however, that it isthe human equivalent of the 'playing dead' reaction displayed by some animals when confronted witha predator from which they cannot escape.

References



Lip, G. Y. H., S. P. Singh, et al., 1998, Key topics in cardiovascular medicineed., BIOS ScientificPublishing, Oxford, UK. pp. 181-184


LEARNING TOPIC - The foetal circulation

The adult circulation contains two separate pumps in series. The right ventricle pumps blood throughthe lungs where it is oxygenated. The left ventricle pumps blood through the body where oxygen isconsumed. In the foetus the circulation differs markedly from the adult since the placenta replacesthe lungs as the source of oxygen while the fetal lungs have no gas exchange function. Furthermoreat birth, after tying and cutting the umbilical cord and the expansion of the lungs with the first breath,the fetal circulation changes rapidly to one approximating to the adult.

The main features of the fetal circulation are as follows.

Two large umbilical arteries leave the iliac artery and carry about 50% of the cardiac output tothe placenta.A single umbilical vein carries oxygenated blood back from the placenta and joins the inferiorvena cava, bypassing the liver.Of the blood returning to the right atrium about half crosses through the foramen ovale, whichconnects the R and L atria, and enters the left atrium.Of the blood pumped out of the right ventricle into the pulmonary artery, about half, instead ofentering the lungs, passes through the ductus arteriosus which connects the pulmonary arteryand the aorta, and enters the systemic circulation.

These differences between fetal and adult circulation occur both because of the anatomicalconnections present in the foetus but also because the uninflated fetal lung has a very high resistanceto blood flow and the fetal systemic circulation has a low resistance because of the placenta.Consequently the pressures on the right side of the heart are higher than on the left (in contrast tothe adult) and blood flows from R to L atrium through the foramen ovale and from the pulmonaryartery to the aorta through the ductus arteriosus.

At birth three main changes occur. The cord is tied and systemic peripheral resistance doublesincreasing pressure in the L heart and aorta. At the first respiratory inflation the resistance topulmonary blood flow falls dramatically, pressure in the R heart drops and flow through the foramenovale and ductus arteriosus falls or reverses. In the next day or so the ductus arteriosus, whichcontains smooth muscle in its wall, normally constricts and is no longer patent. The foramen ovaleacts as a valve so that once L atrial pressure is greater than R it normally prevents flow.

An understanding of these pressure changes is essential to understanding the direction of abnormalflow if any of the normal fetal connections remain patent or other abnormal anatomical connectionsare present in the heart. If right to left shunts occur in the adult then deoxygenated venous blood


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artery to the aorta through the ductus arteriosus.

At birth three main changes occur. The cord is tied and systemic peripheral resistance doublesincreasing pressure in the L heart and aorta. At the first respiratory inflation the resistance topulmonary blood flow falls dramatically, pressure in the R heart drops and flow through the foramenovale and ductus arteriosus falls or reverses. In the next day or so the ductus arteriosus, whichcontains smooth muscle in its wall, normally constricts and is no longer patent. The foramen ovaleacts as a valve so that once L atrial pressure is greater than R it normally prevents flow.

An understanding of these pressure changes is essential to understanding the direction of abnormalflow if any of the normal fetal connections remain patent or other abnormal anatomical connectionsare present in the heart. If right to left shunts occur in the adult then deoxygenated venous bloodbecomes mixed with arterialised blood and cyanosis is possible.

References



Guyton, A. C. and J. E. Hall, 2006, Textbook of medical physiology, 11th ed., Elsevier Saunders,Philadelphia Chapter 83 has a clear account of the fetal circulation and its transition at birth.


LEARNING TOPIC - Treatments for hypertension

BackgroundWe know from population studies that stroke, coronary heart disease (CHD), cardiac failure andprogressive impairment of renal function occur more often and at an earlier age in people with above-average levels of blood pressure (BP). Furthermore, from interventional studies in which patientswith high BP were randomly assigned to antihypertensive therapy or placebo, there is good evidencethat pharmacological intervention reduces the risk of stroke by about 40% and the risk of CHD byabout 15%. The benefits of drug treatment have been demonstrated even in mild hypertension(BP>140/90 mmHg), and in patients with isolated systolic hypertension (especially the elderly). Avariety of antihypertensive drugs is available, affecting one or more components of the equation:

mean BP = cardiac output (CO) x total peripheral resistance (TPR)

(CO = Heart rate x Stroke volume)

BP targetsIn general, the target for well treated hypertension is resting BP <140/90 mmHg in uncomplicatedhypertension, and <130/80 mmHg in those with concomitant diabetes, renal disease or arterialdisease. In practice, combination therapy with two or more of the drugs described below is oftenrequired to meet these targets.

Non-pharmacological therapyWhen a diagnosis of hypertension is made, secondary causes must be sought and treated, andend-organ damage sought and other vascular risk factors measured (eg lipids, weight, blood sugar).The first step in treating hypertension is instituting lifestyle measures including sensible diet, weightloss where appropriate, salt restriction and a regular exercise program. Where these measures fail orare insufficient to meet BP targets (as above), drug therapy should be considered.

Drug therapy

First line agents

Calcium AntagonistsThis family of drugs, all of which block calcium channels, can be broadly divided into thedihydropyridines (eg nifedipine, felodipine, amlodipine) and the non-dihydropyridines (egverapamil and diltiazem). Nifedipine-like drugs act exclusively on vascular smooth muscle,lowering BP by vasodilation, whereas verapamil and diltiazem have additional effects on theheart, reducing AV nodal conduction and myocardial contractility. Dihydropyridines induce reflexsympathetic activation, which often gives rise to the typical side effects of tachycardia, flushingand headache, whereas the fall in BP with verapamil or diltiazem is associated with a reduction(or little change) in heart rate. Dihydropyridines are particularly suitable for combination with abeta blocker, but verapamil and diltiazem are contraindicated in combination with beta blockersbecause of the risks of profound bradycardia and heart failure. All the calcium antagonists(except amlodipine) have an intrinsically short half-life, so they are often formulated in aSlow-Release system to facilitate fewer daily doses.

1.


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dihydropyridines (eg nifedipine, felodipine, amlodipine) and the non-dihydropyridines (egverapamil and diltiazem). Nifedipine-like drugs act exclusively on vascular smooth muscle,lowering BP by vasodilation, whereas verapamil and diltiazem have additional effects on theheart, reducing AV nodal conduction and myocardial contractility. Dihydropyridines induce reflexsympathetic activation, which often gives rise to the typical side effects of tachycardia, flushingand headache, whereas the fall in BP with verapamil or diltiazem is associated with a reduction(or little change) in heart rate. Dihydropyridines are particularly suitable for combination with abeta blocker, but verapamil and diltiazem are contraindicated in combination with beta blockersbecause of the risks of profound bradycardia and heart failure. All the calcium antagonists(except amlodipine) have an intrinsically short half-life, so they are often formulated in aSlow-Release system to facilitate fewer daily doses.Angiotensin Converting Enzyme (ACE) InhibitorsThis family of drugs are all broadly similar in terms of their antihypertensive profile, egcaptopril, enalapril, and perindopril. They block the enzymatic conversion of angiotensin I toangiotensin II (ANG II) which is a potent vasoconstrictor hormone produced not only in thecirculation but also in many organs. Thus, inhibition of both circulating and tissue-based ACEcontributes to the antihypertensive effect. All ACE inhibitors except captopril and lisinopril areprodrugs, requiring conversion in the liver to the active diacid metabolite, eg enalaprilat, and thereduction in BP following ACE inhibition is not accompanied by any reflex tachycardia. 15-20%of patients complain of a dry cough, and renal function may deteriorate, especially in patientswith renovascular hypertension. ACE inhibitors have useful ancillary properties, eg reducing LVHand improving arterial compliance. Their antihypertensive effects are enhanced byco-administration of a diuretic.

2.

Angiotensin receptor-antagonistsThis is a relatively new group of antihypertensive agents that competitively block the AT1subtype of angiotensin II receptors on vascular smooth muscle. Examples include Iosartan andirbesartan. These drugs appear to have similar efficacy to ACE inhibitors but are associated withless cough. Like ACE inhibitors, they appear to have particular renoprotective effects in subjectswith diabetes.

3.

DiureticsThiazide diuretics are effective antihypertensive agents, eg hydrochlorothiazide, indapamide andbendrofluazide. They are particularly useful in the elderly. Thiazides have a tendency to causeundesirable metabolic side effects, eg hypokalaemia, hyperglycaemia and hyperuricaemia, butsuch problems are usually of little clinical significance when the drugs are used in low doses.

Nevertheless, they are best avoided in patients with diabetes or gout. Use of K + supplements

and/or K + - sparing diuretics is usually unnecessary, but serum K + should be monitored. Thefall in BP is due, at least in part, to natriuresis and diuresis, but thiazides probably also havedirect vasodilator effects that contribute to their antihypertensive mechanism. They are cheap,as effective and well tolerated as newer types of antihypertensive, and there is strong evidenceto support their benefits in reducing mortality from hypertensive complications.

4.

Beta-Adrenoceptor AntagonistsAll beta blockers are broadly similar in terms of their antihypertensive efficacy, althoughpharmacologically some are more selective for b1-receptors (eg atenolol and metoprolol), someare more lipid soluble (eg propranolol) and some have intrinsic sympathomimetic activity (iepartial agonists eg oxprenolol). Beta blockers primarily lower BP by reducing heart rate andcardiac output, but other mechanisms may also contribute, eg inhibition of renin release. Thesedrugs are useful either as monotherapy or in combination with other agents, eg diuretics ordihydropyridine calcium antagonists. All beta blockers are contraindicated in patients withreversible obstructive airways disease (eg asthma) or peripheral vascular disease, and they areoften avoided in patients with diabetes. Typical side effects of beta blocker therapy (in 15-20%of patients) include tiredness, impotence, exercise limitation, excessive bradycardia or heartblock, and sleep disturbance.

5.

Second line agents

Other DrugsOther drugs used occasionally include alpha-1 adrenoceptor antagonists (eg prazosin,terazosin), which are vasodilators; centrally-acting drugs (eg clonidine and methyldopa) whichdecrease sympathetic outflow; and hydralazine, which is a direct relaxant of vascular smoothmuscle.

1.

Author: Professor David Celermajer, Medicine

LEARNING TOPIC - Ventricular arrhythmias

Ventricular arrhythmias are disturbances of the electrical excitation of the ventricular myocardiumthat affect the rate and coordination of contraction. Disturbed rate or coordination may severely


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muscle.

Author: Professor David Celermajer, Medicine

LEARNING TOPIC - Ventricular arrhythmias

Ventricular arrhythmias are disturbances of the electrical excitation of the ventricular myocardiumthat affect the rate and coordination of contraction. Disturbed rate or coordination may severelyreduce the heart's overall pumping efficiency.

Pumping efficiency is most affected by mean ventricular rate, the optimal rate varying with the stateof the peripheral circulation and venous return, e.g. rest v exercise. Pumping efficiency is alsoaffected by the timing of atrial contraction prior to ventricular contraction. This is particularlyimportant when the ventricles are scarred of thickened and do not relax properly in diastole ('diastolicdysfunction'). Pumping efficiency is also affected slightly by disturbed His-Purkinje conduction so thatthe QRS duration is prolonged and the ventricular wall does not contract synchronously, but this isusually important only when the heart has reduced reserves of pumping power for other reasons.

Very rapid ventricular rates shorten diastole and reduce coronary blood flow, leading to myocardialischaemia. At the extremes the heart may have no cardiac output ('cardiac arrest') with no electricalactivity ('asystole'), or because the beating is very rapid (300/min, 'ventricular flutter') or totallyun-coordinated and chaotic ('ventricular fibrillation').

Ventricular arrhythmias are classified into bradycardias (slow) or tachycardias (fast). VentricularBradycardia is the result of failure of conduction of the normal electrical impulses from the sinus oratrioventricular node to the ventricles. With complete failure of conduction, the normal His-Purkinjesystem depolarises spontaneously at about 40/min (escape rhythm) but may be slower or display noautomaticity at all if diseased. Treatment is by artificial electronic pacemaker, which may pace theright ventricle only, both the atria and ventricles ('dual chamber') to relate atrial and ventricularcontraction times appropriately, and both the right and left ventricles simultaneously ('bi-ventricular')to ensure that the left ventricle contraction is synchronous. Emergency treatment for bradycardia withloss of conciousness prior to instituting electrical pacing is a beta1 adrenergic stimulant, e.g.isopropyl nor-adrenaline ('Isuprel' ~5 mcg/ min I.V. infusion), just sufficient to prevent syncope andoliguria.

Ventricular tachycardia is due to electrical depolarisations arising within the ventricles themselves.Because ventricular depolarisation is abnormal and not usually via the His Purkinje system the QRScomplexes in the ECG are larger, abnormal in shape and of longer duration than normal. The atria maycontinue to beat normally, unrelated to the ventricles, or may be entrained by backward (retrograde)conduction through the atrioventricular node.

Ventricular tachycardia occurrs most frequently as a result of an electrical depolarisation wavefollowing a constant circular course in the ventricular myocardium ('re-entrant tachycardia') andexciting the ventricles repeatedly. The refractory period of the ventricular myocardium normallyprevents this arrhythmia. If conduction through the myocardium is slowed, e.g. by bands of scartissue or ischaemic myocardium, or the ventricles are enlarged or hypertrophied so that longerpathways and conduction times are possible this arrhythmia may occur. It can be precipitated bypremature ventricular ectopic beats, or by programmed ventricular electrical stimulation in theelectrophysiology laboratory. The re-entry electrical wave may follow a constant anatomical path('ventricular tachycardia') or break up into multiple uncoordinated re-entry loops ('ventricularfibrillation'). Spontaneous cessation will occur if the electrical waves cannot propogate the electricalwavefront to any adjacent excitable myocardium.

Treatment is by modifying sympathetic tone with beta1 adrenergic blockade, by modifying theconduction time and refractory period of the myocardium with other 'anti-arrhythmic' drugs, byinterrupting the re-entry loops by rapid electrical pacing, electrically depolarising all the ventricularmyocardium at once (bi-phasic defibrillation), or by destroying localised potential re-entry pathwaysby electro-cautery or surgery.

A rarer cause of abnormal rapid ventricular tachyarrhythmias is abnormality in myocardial cellmembrane electrical properties leading to repetitive action potentials. These are likely in acutemyocardial ischaemia, some drug intoxications (e.g. digoxin), and genetic abnormalities in myocardialcell membrane ion channels, sometimes associated with long QT interval in the resting ECG orcongenital deafness due to the same ion channel defects being expressed in the hair cells of thecochlear.

References



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A rarer cause of abnormal rapid ventricular tachyarrhythmias is abnormality in myocardial cellmembrane electrical properties leading to repetitive action potentials. These are likely in acutemyocardial ischaemia, some drug intoxications (e.g. digoxin), and genetic abnormalities in myocardialcell membrane ion channels, sometimes associated with long QT interval in the resting ECG orcongenital deafness due to the same ion channel defects being expressed in the hair cells of thecochlear.

References



Berne, R. M., 2004, Physiology, 5th ed., Mosby, St. Louis

Boon, N. A. and S. Davidson, 2006, Davidson's principles & practice of medicine, 20th ed.,Elsevier/Churchill Livingstone, Edinburgh ; New York

Zipes, D. P. and E. Braunwald, 2005, Braunwald's heart disease : a textbook of cardiovascularmedicine, 7th ed., W.B. Saunders, Philadelphia, Pa.[Available as a E-Book]

Author: Emeritus Professor John Uther, Cardiology, Western Clinical School


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cardio learning topics block 5

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