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Cardiovascular disease (cardio refers to the heart and vascular refers to the blood circulation system) is the general term given to conditions that include:

• Problems with the blood vessels that supply the heart muscle (coronary artery disease)
• High blood pressure (hypertension)
• Problems with the blood vessels that supply the brain (stroke)
• Abnormalities in the structure of the heart affecting the valves and muscle of the heart (eg cardiomyopathy) and other heart 'defects'; when these are present at birth they are called congenital heart defects
• Problems with the 'electrical' system in the heart that controls the heart beat (arrhythmias)
• Problems with other arteries in the body, such as the aorta (the main artery that leads from the heart)

In some cases of LQTS, the information in the genes contributes to the development of cardiovascular disease. This is more likely when there are a number of affected members of a family and symptoms of the condition occur at an early age

In most cases of LQTS, where there is a family history of cardiovascular disease, the genetic component appears to be a 'susceptibility' factor, rather than a direct cause. That is, the disease is a multifactorial condition (see Genetics Fact Sheet 11) where both inherited genetic predisposition to develop the condition and environmental triggers are involved.

Our genes are part of chromosomes and provide the information for our bodies to grow and develop, and to work properly throughout our life (see Genetics Fact Sheet 1). When the information in the genes is changed in some way, the information sent to the cells may be different.

If the information is changed so that the gene product in the cell is impaired, reduced or absent, the gene change is described as a mutation. Mutations are changes in genes that make the gene faulty (see Genetics Fact Sheet 4).

Genetic predisposition means that an individual has inherited from a parent a faulty gene copy that does not cause a problem directly but makes them more susceptible to developing the condition later in life when particular environmental factors that trigger the condition are present (see Genetics Fact Sheet 11).

We all have two copies of all our genes in our cells and when one copy of a gene is faulty, it may not cause a problem as the other gene copy still sends the correct message to the cells to make the gene product. Even if the gene change is major, other genes in the cell may still enable the cell to function normally.

• In some cases, changes can occur during life in the other gene copy or to the other genes, caused by as yet largely unknown environmental factors
• In other cases, it is not clear how the environmental factors interact with the inherited faulty gene copy

However, it is clear that if the environmental triggers can be identified where there is a genetic susceptibility to develop a cardiac condition, manipulation of the environmental factor or preventing its interaction with the genetic make-up will enable preventive strategies for cardiac conditions to be developed.

It is therefore important to determine both the genetic basis of cardiovascular conditions to be able to identify those who may wish to know of their susceptibility, as well the environmental triggers.

This Fact Sheet discusses the role of genetics in predisposition to cardiovascular conditions where there is a problem with the electrical control of the heartbeat.

• Genetics Fact Sheet 53 discusses an inherited tendency to have high cholesterol that leads to coronary artery disease (familial hypercholesterolaemia)
• Genetics Fact Sheet 54 discusses the role of genetics in predisposition to cardiomyopathies
• Genetics Fact Sheet 56 discusses the genetic aspects of hypertension, congenital heart defects and inherited conditions of connective tissue with cardiovascular effects

The heartbeat is a sound generated by the contraction and relaxation rhythm of the four chambers of the heart: two atriums and two ventricles (Figure 55.1). This sound is powered by an electrical signal (impulse). An average heart beats 100,000 times a day, pumping some 500 litres of blood through its chambers to the rest of the body and then back to the heart.

Figure 55.1: Normal heart. RA = right atrium, LA = left atrium, RV and LV = right and left ventricles.

The electric signal, generated by the heart itself as it contracts, is produced by the flow of charged chemicals (potassium, sodium and calcium) called ions, within the cells of the heart. The ions flow in and out of the heart's cells through ion channels.

Doctors can record the electrical signal produced by the ions on a machine called the electrocardiogram (ECG, or EKG) by placing electrodes on the skin of the chest. The machine makes a tracing of the signal, called a waveform.

The different parts of the waveform are represented by the letters P, Q, R, S and T (Figure 55.2).

Figure 55.2: Normal heart signal as measured by an ECG. The Q-T interval is longer in long QT syndrome.

Many forms of heart disease are caused by interruptions to the normal contract-relax cycle and cause abnormally fast or unusually slow heart rates and changes in the waveform produced on the ECG.

• These conditions are called cardiac arrhythmias: the heart pumps less effectively, so that not enough blood reaches the brain and other vital organs. When the body's blood flow is inadequate, the person can faint or suffer chest pain
• For example, by looking at the waveform, doctors can see the time it takes for the electrical signal to activate and inactivate the lower chambers of the heart (the ventricles). This is called the Q-T interval (Figure 55.2)

Long qt syndrome (LQTS)

Long QT syndrome (LQTS) is a group of conditions where there is a longer QT interval on an ECG than usual. This prolonged Q-T interval can increase the risk for a type of arrhythmia that can lead to ventricular fibrillation: fast, chaotic heartbeats due to rapid, uncoordinated contractions in the muscle fibres of the ventricles.

Ventricular fibrillation means that the heart cannot pump enough oxygen-rich blood to the rest of the body, causing the symptoms of LQTS which include fainting (syncope) and, in some cases, cardiac arrest and sudden death. This can occur during or following exercise in otherwise fit and healthy young people. LQTS is an important cause of unexpected sudden death, especially in children and young adults. Symptoms usually develop during childhood, but may occur at any age.

LQTS affects about 1 in 5000 people.

LQTS is a group of cardiac arrhythmias due to problems in the ion channels of the heart cells. The condition can be caused by more than 50 medications, many of them common, as well as part of other medical conditions.

In other cases of LQTS there is an inherited predisposition. Changes in at least eight genes have been identified as causing predisposition to LQTS. The condition however may never develop unless triggered by environmental factors. These factors may include certain medications, illnesses that could result in low blood potassium levels and strenuous exercise.

Two major clinical long QT syndromes have been characterised of which Romano-Ward syndrome is the most common.

A change in one of five different genes that make the gene faulty results in an increased risk for this form of LQTS to develop. If a person has one faulty LQTS gene copy and the other partner LQTS gene copy is working, they are carriers of the faulty LQTS gene: they are genetic carriers for LQTS.

• Genetic carriers for LQTS are susceptible (predisposed) to ventricular fibrillation leading to cardiac arrest and sudden death
• Just having a faulty LQTS gene copy is not enough for the syndrome to develop

Two factors influence the pattern of inheritance of LQTS in affected families.

1. The five different genes are all located on autosomes (one of the numbered chromosomes)
2. The effects of changes in the genes involved are 'dominant' over the information in the working copy of the genes on the partner chromosomes (see Genetics Fact Sheets 1, 4 & 5)

The pattern of inheritance in families of the faulty genes causing predisposition to LQTS is therefore described as autosomal dominant inheritance (see Genetics Fact Sheet 9).

In Figure 55.3 the autosomal dominant faulty gene causing predisposition to LQTS is represented by 'D'; the working copy by 'd'. Where one of the parents has LQTS (or is predisposed to LQTS) due to faulty LQTS gene, there are four possible combinations of the genetic information that is passed on by the parents.

Figure 55.3: Autosomal dominant inheritance when one parent has a faulty Long QT syndrome (LQTS) gene copy.
The faulty Long QT syndrome (LQTS) gene copy is represented by 'D; the working copy by 'd'.

This means that, in every pregnancy, there is

• An equal chance ie. 1 chance in 2 (or 50% chance) that their child will inherit a copy of the faulty LQTS gene and will therefore be susceptible to the syndrome and cardiac arrest
• An equal chance ie. 1 chance in 2 (or 50%) that their child will inherit the working copy of the gene from his/her affected parent as well as a working copy from his/her unaffected parent. In this case, the child will not be any more susceptible to cardiac arrhythmia than anyone in the community

While Figure 55.3 shows the father as the parent carrying the faulty LQTS gene, the same situation would arise if it was the mother. A faulty LQTS gene can be inherited from either the mother or the father.

The usual method of diagnosis of LQTS is by a cardiologist, involving ECG and exercise tests. Treatment may include drug therapy; an implantable defibrillator may be indicated for some individuals.

People with a strong family history of LQTS can seek advice from their local genetic counselling service. Their risk of developing LQTS can be estimated from their family history and discussed in more detail (see Genetics Fact Sheet 3).

The genetic counselling team may be able to:

• Clarify their chance of developing LQTS based on their family history
• Answer any questions they have about their family history of cardiac arrhythmia
• Discuss what medical check-ups are appropriate
• Discuss the limitations, potential benefits, disadvantages and appropriateness of genetic testing (see Genetics Fact Sheet 21)

Genetic testing for mutations in the LQTS genes involves:

• First identifying the mutation in a family member who has or had LQTS. This is called a mutation search and may take considerable time

Second, and only if a mutation is found, testing may be possible for other family members without LQTS, to determine if they have inherited the faulty gene. This is called predictive genetic testing (see Genetics Fact Sheet 21).

Other Genetics Fact Sheets referred to in this Fact Sheet: 1, 3, 4, 5, 9, 11, 21, 53, 54, 56

Australian Institute of Health and Welfare (AIHW). Chronic diseases and associated risk factors in Australia, 2001 [online]. Canberra. Available from: http//www.aihw.gov.au/publications. [Accessed June 2007]

Cardiac Society of Australia and New Zealand. (2005). Guidelines for the diagnosis and management of familial long qt syndrome [online].Available from: http://www.csanz.edu.au/guidelines/practice/Long_QT_guidelines.pdf . [Accessed June 2007]

Doolan A, Langlois N and Semsarian C. (2004). Causes of sudden cardiac death in young Australians. Medical Journal of Australia, 180:110-112.

Harper P. (2004). Practical Genetic Counselling. London: Arnold

Milewicz D and Seidman C, (2000). Genetics of cardiovascular disease. Circulation 102, Supplement: IV-103-IV-111.

National Organisation for Rare Disorders (NORD) [online]. Available from: http://www.rarediseases.org/. [Accessed June 2007]

Online Mendelian Inheritance in Man, OMIM (TM). McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins University (Baltimore, MD) and National Center for Biotechnology Information, National Library of Medicine (Bethesda, MD) [online]. Available from: http://www.ncbi.nlm.nih.gov/omim/ [Accessed June 2007]

Priori S, et al. (1999). Genetic and molecular basis of cardiac arrhythmias: Impact on clinical management. European Heart Journal, 20: 174-195

Semsarian C. (2002). Unravelling disease genes in cardiovascular medicine: from bench to bedside. Cardiac Society of Australia and New Zealand Newsletter On the Pulse 14(1)

June 2007 (1st Ed)

Author/s: A/Prof Kristine Barlow-Stewart

Acknowledgements this edition: Gayathri Parasivam; Prof Jon Emery A/Prof Sylvia Metcalfe