Long-QT syndrome

Definition

Long-QT syndrome is a family of genetic or acquired disorders that causes cardiac arrhythmias, irregularities in the electrical activity of the heart, that can lead to cardiac arrest and sudden death. The syndrome is characterized by a longer-than-normal QT interval on an electrocardiogram.

Description

Long-QT syndrome (LQTS) is one of the sudden arrhythmia death syndromes (SADS). It is a major cause of sudden, unexplained death in children and young adults, resulting in as many as 3,000–4,000 deaths per year in the United States. Its symptoms include seizures or fainting, often in response to stress.

LQTS was first described by C. Romano and coworkers in 1963 and by O. C. Ward in 1964, as a syndrome that was almost identical to Jervell and Lange-Nielsen syndrome , but without congenital deafness. Therefore, LQTS also is known as Romano-Ward syndrome or Ward-Romano syndrome.

LQTS involves irregularities in the recharging of the heart's electrical system that occurs after each heartbeat or contraction. The QT interval is the period of relaxation or recovery that is required for the repolarization, or recharging, of the electrical system following each heart contraction. The depolarization that causes the heart to contract and the repolarization occur via the opening and closing of potassium, sodium, and calcium ion channels in the membranes of heart cells. As sodium channels in the heart open, positively charged sodium ions flow into the cells, making the inner surfaces of the cell membranes more positive than the outside and creating the action potential, or electrical charge. During depolarization, the sodium channels shut and, after a delay, potassium channels open and allow positively charged potassium ions to move out of the cells, returning the cell membranes to their resting state, in preparation for the next heart contraction.

Individuals with LQTS have an unusually long QT interval. If the electrical impulse for the next contraction arrives before the end of the QT recovery period, a specific arrhythmia arises in the ventricles, or lower chambers, of the heart. This arrhythmia is called polymorphous ventricular tachycardia, meaning fast heart (above 100 beats per second), or torsade de pointes, meaning turning of the points. A normal heartbeat begins in the right atrium of the heart and progresses down to the ventricles. In ventricular tachycardia, the heartbeat may originate in the ventricle. Usually this very fast and abnormal heartbeat reverts to normal. If it does not, it leads to ventricular fibrillation, in which the heart beats too fast, irregularly, and ineffectively. This can result in cardiac arrest and death. Variations in the QT interval from one heart cell to another also can cause arrhythmias and ventricular fibrillation in LQTS.

LQTS usually results from changes, or mutations, in one of six or more genes. These genes encode proteins that form the ion channels in the heart. Although such mutations can arise spontaneously in an individual, they are most often passed on from parent to offspring. Thus, LQTS usually runs in families.

Acquired LQTS is caused by factors other than genetic inheritance or mutation. Many different medications, including heart medicines, antibiotics, digestive medicines, psychiatric drugs, and anti-histamines, as well as certain poisons, can result in LQTS. Some of these drugs block potassium ion channels in the heart. Diuretic medications can cause LQTS by lowering levels of potassium, magnesium, and calcium in the blood. Mineral imbalances, resulting from chronic vomiting, diarrhea, or starvation, also can result in LQTS, as can strokes or other neurological problems or alcoholism . However, since only certain individuals develop LQTS under these circumstances, genetics also may play a role in the acquired disorder.

Genetic profile

Although all of the genes that are known to be involved in LQTS encode proteins that form sections or subunits of ion channels through cellular membranes, the type of LQTS depends on the specific gene defect.

Most forms of LQTS are autosomal dominant genetic disorders . Thus, the genes that cause LQTS are carried on one of the 22 pairs of autosomal chromosomes , rather than on the X or Y sex chromosomes. Furthermore, only one copy of the mutant gene is necessary for the development of LQTS. Thus, an individual who inherits a normal gene copy from one parent and an abnormal gene copy from the other parent is likely to have LQTS. The children of an individual with one normal gene copy and one mutated copy have a 50% chance of inheriting LQTS.

LQT1 and LQT5

LQT1 is the most common form of LQTS. It is caused by any of a number of gene mutations in the KVLQT1 (KvLQT1) gene located on the short arm of chromosome 11. KVLQT1 also is known as KCNQ1. This gene codes for an alpha-subunit of a voltage-gated potassium ion channel that is highly expressed in the heart. Protein subunits encoded by a mutant KVLQT1 gene may combine with protein subunits encoded by a normal KVLQT1 gene to form defective potassium channels. Although most mutations in KVLQT1 are dominant, some mutations in this gene may be recessive. In these cases, LQTS is present only in individuals with two abnormal KVLQT1 genes, one inherited from each parent.

The KCNE1 (MinK or IsK) gene on chromosome 21 codes for the beta or regulatory subunit that combines with the alpha-subunit encoded by KVLQT1. Together, they form the ion channel that is responsible for the cardiac I_Ks) potassium current. This is a slow ion channel that is activated by depolarization of the action potential of the heart, which causes the channel to open and potassium ions to move freely out of the cells during repolarization. Mutations in KCNE1 also can cause a defective potassium channel protein, resulting in the LQT1 form of LQTS. However, LQTS resulting from mutations in KCNE1 may be called LQT5.

Jervell and Lange-Nielsen syndrome is a very rare disorder in which an individual has two copies of an abnormal KVLQT1 or KCNE1 gene, one inherited from the mother and the other from the father. This syndrome is characterized by congenital deafness as well as a prolonged QT interval.

LQT2 and LQT6

LQT2 is the second most common form of LQTS. Mutations in the HERG gene (so-named because it is the human equivalent of a fruit fly gene called ether-a-go-go) can result in LQT2. HERG, located on chromosome 7, encodes a protein subunit of another potassium ion channel in the heart. Mutations in HERG result in loss of the potassium current called I_Kr.

The KCNE2 or MiRP1 (for MinK-related) gene is located next to MinK (KCNE1) on chromosome 21. It encodes a regulatory beta-subunit protein that combines with the protein encoded by HERG to form a potassium ion channel. The form of LQTS resulting from mutations in the KCNE2 gene is known as LQT6.

Mutations in potassium channel genes reduce the number of functional potassium channels in the heart and lengthen the QT interval by delaying depolarization. Almost all cases of inherited LQTS result from mutations in KVLQT1 or KCNE1, causing LQT1, or mutations in HERG or KCNE2, causing LQT2.

LQT3

Mutations in the SCN5A gene can result in an uncommon form of LQTS known as LQT3. SCN5A, on chromosome 3, encodes a component of a cardiac sodium ion channel. Some mutations in this gene prevent the channel from being inactivated. Thus, although the channel opens normally and sodium ions flow into the cells with each contraction, the channel does not close properly. Sodium ions continue to leak into the cells, thereby prolonging the action potential. A different mutation in SCN5A decreases the flow of sodium ions into the cells, shortening the action potential and causing a distinct condition known as Brugada syndrome.

Other types of LQTS

Mutations in yet another gene, located on chromosome 4, can result in a type of LQTS known as LQT4.

A small number of individuals with LQTS have mutations in more than one of the known genes. Some families with inherited LQTS lack mutations in any of these known genes, suggesting the existence of other genes that can cause LQTS. Furthermore, individuals with identical LQTS genes may differ significantly in the severity of their symptoms, again suggesting the existence of other genes that can cause or modify LQTS.

Demographics

Large-scale studies of LQTS, such as the International Registry for LQTS established in 1979, have revealed that the disorder is much more prevalent than was believed originally. Inherited LQTS is estimated to occur in one out of every 5,000-10,000 individuals and it occurs in all racial and ethnic groups. LQTS may result in fetal death, may account for some cases of sudden infant death syndrome (SIDS), and has been implicated in many instances of sudden death and unexplained drownings among individuals who were previously without symptoms.

As an autosomal, non-sex-linked genetic disorder, LQTS should affect males and females in equal numbers. However, it appears to be more prevalent among women. Nearly 70% of the time, a female is the first member of a family to be recognized as having LQTS. Females are two

to three times more likely than males to exhibit symptoms of LQTS. However, in general, males manifest symptoms of LQTS at an earlier age than females. At puberty, the QT interval shortens in males; whereas in females it stays the same or shortens only slightly. Therefore, unaffected women have slightly longer QT intervals than unaffected men. Men with LQT1 or LQT2 have shorter QT intervals than either women or children with these two forms of the disorder. Women also are more likely than men to develop drug-induced or acquired LQTS. These gender-related differences may be due to the effects of the female hormone estrogen on the regulation of cardiac ion channels, particularly potassium channels.

Signs and symptoms

Sudden death

Tragically for many individuals with LQTS, sudden death by cardiac arrest is the first symptom. For this reason, LQTS sometimes is referred to as a "silent killer." Approximately one-third of deaths from LQTS are not preceded by any symptoms of the disease. At least one-third of the individuals carrying a gene variant that causes LQTS do not exhibit any symptoms.

SIDS is the leading cause of death among infants between the ages of one month and one year. SIDS claims the lives of one or two out of every 1,000 infants. About 7,000 babies per year die of SIDS in the United States alone. In 1998, the results of a very large study, the Multicenter Italian Study of Neonatal Electrocardiography and SIDS, conducted under the direction of Peter J. Schwartz of the University of Milan, found that a large number of SIDS victims had prolonged QT intervals.

Syncope and seizures

Dizziness, sudden loss of consciousness or fainting spells (syncopes), or convulsive seizures are common symptoms of LQTS. These occur because the heart is unable to pump sufficient blood to the brain. Following a loss of consciousness or syncope, the torsade de pointes rhythm usually reverts spontaneously to a normal rhythm within one minute or less and the individual regains consciousness. These symptoms may appear first during infancy or early childhood, although sometimes no symptoms are evident until adulthood. Some individuals may experience syncopal episodes from childhood on; whereas others may experience one or two episodes as children, with no recurrence throughout adulthood. On average, males with LQTS first exhibit symptoms at about age eight and females at about age 14. These symptoms usually occur upon awakening, during strenuous physical activity, or during moments of excitement or stress.

Other symptoms

Newborn infants and children under the age of three with LQTS may exhibit slower than normal resting heart rates. Individuals with LQTS may experience irregular heartbeats accompanied by chest pain.

Gene-specific symptoms

Symptoms of LQTS vary depending on the specific gene mutation . Certain mutations in the KVLQT1 gene that cause LQT1 may result in arrhythmias when an individual is under stress. Exercise is a major trigger for cardiac events in LQT1. Swimming can trigger syncopic episodes and appears to be a gene-specific trigger in individuals with KVLQT1 mutations. Drowning is the second most common cause of accidental death in children and young adults and about 10% of such drownings are unexplained. Thus, LQT1 may account for many unexplained drownings and near-drownings.

Sudden loud noises, such as telephones or alarm clocks, are more likely to trigger arrhythmias and syncopic episodes in individuals with LQT2. Cardiac events, including syncope, aborted cardiac arrest, and sudden death, are more common among individuals with LQT1 or LQT2 than among those with LQT3. However, cardiac events are more likely to be lethal in individuals with LQT3. Certain variants of the SCN5A gene that cause LQT3 result in abnormal heart rhythms during sleep.

Individuals with some of the variants of the KCNE2 gene that cause LQT6 may be adversely affected by exercise and some medications.

Diagnosis

Electrocardiogram

A diagnosis of LQTS most often comes from an electrocardiogram (ECG or EKG). An ECG records the electrical activity of the heart, using electrical leads placed at specific sites on the body. The electrical activity due to the depolarization and repolarization of the heart is recorded by each lead and added together. The recordings, on paper or on a monitor, show a series of peaks, valleys, and plateaus.

The QRS complex is a sharp peak and dip on the ECG that occurs as the electrical impulses fire the cells of the ventricles, causing contraction and depolarization of the action potential. The torsade de pointes, or turning of the points, refers to these spikes in the QRS complex. Sometimes it is possible to diagnose torsade de pointes from an ECG. The T wave on the ECG occurs as the cells recover and prepare to fire again with the next heartbeat. Thus, the T-wave represents the repolarization of the ventricles. The QT interval on the ECG is the period from the start of the depolarization of the ventricles (Q), as the electrical current traverses the ventricles from the inside to the outside, through the repolarization of the ventricles (T), as the current passes from the outside to the inside. Thus, the QT interval represents the firing and recovery cycle of the ventricles. In LQTS, the QT interval on the ECG may be a few one-hundredths of a second longer than normal. A QT interval that is longer than 440 milliseconds is considered to be prolonged. There also may be abnormalities in the T-wave of the ECG.

ECGs may vary depending on the specific mutation that is the cause of the LQTS. Furthermore, as many as 12% of individuals with LQTS may have normal-appearing or borderline-normal QT intervals on an ECG. An individual's ECGs can vary, and additional ECGs or ECGs performed during exercise may reveal an abnormal QT interval. ECGs of parents or siblings also may contribute to a diagnosis, since one parent, and possibly siblings, may carry a gene variation that causes LQTS and, therefore, may exhibit a prolonged QT interval on an ECG.

Other diagnostic methods

Children with LQTS may exhibit a low heart rate; specifically, a resting heart rate that is below the second percentile for their age. A fast heart rate of 140-200 beats per minute may indicate tachycardia resulting from LQTS. Convulsive seizures due to LQTS sometimes are misdiagnosed as epilepsy , particularly in children.

Some individuF with LQTS may have low levels of potassium in their blood.

Genetic diagnosis

Some 200 specific changes have been found in the genes that are responsible for LQTS. Furthermore, as many as one-half of the individuals diagnosed with LQTS do not carry any of the known genetic variations. Thus, it can be difficult to diagnose LQTS on the basis of genetic testing . However, when family members are known to carry a specific LQTS gene mutation, genetic testing may be used to diagnose LQTS in other family members.

Treatment and management

Beta-blockers

Beta-adrenergic blockers, or beta-blockers, are the most common treatment for the ventricular arrythmia resulting from LQTS. Propranolol is the most frequently prescribed drug, although nadolol also is used. Propranolol lowers the heart rate and the strength of the heart muscle contractions, thereby reducing the oxygen requirement of the heart. Propranolol also regulates abnormal heart rates and reduces blood pressure.

Beta-blockers are very effective for treating LQT1, as well as many cases of LQT2. Thus, approximately 90% of individuals with LQTS can be treated successfully with these drugs. However, since the prophylactic effects disappear within one or two days of stopping the beta-blocker, treatment with these drugs usually lasts for life. Since the first symptom of LQTS may be sudden death, younger individuals with prolonged QT intervals or with family histories of LQTS commonly are treated with beta-blockers even in the absence of symptoms.

Beta-blockers such as propranolol are considered to be safe medications. Any side effects from propranolol are usually mild and disappear once the body has adjusted to the drug. However propranolol and other beta-blockers can interact dangerously with many other medications.

Other drugs

As knowledge of the causes of LQTS increases, other drugs may prove to be more effective for treating some forms of LQTS. For example, mexiletine, a sodium-channel blocker, is used to shorten the QT interval in individuals with LQT3 that results from mutations in the SCN5A gene.

Potassium

Elevating the levels of blood potassium may relieve symptoms of LQTS in individuals with mutations in potassium channel genes. For example, increased blood potassium raises the outward potassium current in the HERG-encoded channel. Thus, treatment with potassium can compensate to some extent for the shortage of functional potassium ion channels in individuals with LQT2, thereby shortening the QT interval.

Surgical intervention

Left cardiac sympathetic denervation, the surgical cutting of a group of nerves connecting the brain and the heart, may reduce cardiac arrhythmias in individuals with LQTS. Pacemakers or automatic implanted cardioverter defibrillators (AICDs) also are used to regulate the heartbeat or to detect and correct abnormal heart rhythms. Sometimes, a pacemaker or AICD is used in combination with beta-blockers.

Preventative measures

Since the likelihood of developing symptoms of LQTS after about age 45 is quite low, individuals who are at least middle-aged when first diagnosed may not be treated. However, all individuals that have been diagnosed with LQTS must avoid reductions in blood potassium levels, such as those that occur with the use of diuretic drugs. Furthermore, individuals with LQTS must avoid a very long list of drugs and medications which can increase the QT interval or otherwise exacerbate the syndrome.

Infants in LQTS families should be screened with ECGs and monitored closely, due to the 41-fold increase in the risk of SIDS.

Individuals with LQTS usually are advised to refrain from competitive sports and to practice a "buddy" system during moderate exercise. Family members may be advised to learn cardiopulmonary resuscitation (CPR) in case of cardiac arrest.

Prognosis

The prognosis usually is quite good for LQTS patients who receive treatment. Symptoms may disappear completely and, often, at least some of the ECG abnormalities revert to normal. In contrast, the death rate for LQTS can be very high among untreated individuals.

Pregnancy

Women with LQTS usually do not experience an increase in cardiac events during pregnancy or delivery. However, they may experience an increase in serious episodes in the months following delivery. This is especially true for women who have experienced syncopic episodes prior to pregnancy. This increase in symptoms may be due to the physical and emotional stress of the postpartum period. Women who receive beta-blocker therapy during pregnancy and following delivery experience far fewer cardiac events. Beta-blockers do not appear to adversely affect a pregnancy, nor do they appear to harm the fetus.

Resources

PERIODICALS

Ackerman, M.J., D.J. Tester, and C.J. Porter. "Swimming, a Gene-Specific Arrhythmogenic Trigger for Inherited Long QT Syndrome." Mayo Clinic Proceedings 74 (November 1999): 1088–94.

Li, H., J. Fuentes-Garcia, and J.A. Towbin. "Current Concepts in Long QT Syndrome." Pediatric Cardiology 21 (November 2000): 542–50.

Wang, Q., Q. Chen, and J.A. Towbin. "Genetics, Molecular Mechanisms and Management of Long QT Syndrome." Annals of Medicine 30, no. 1 (February 1998): 58–65.

ORGANIZATIONS

Cardiac Arrhythmias Research and Education Foundation, Inc. 2082 Michelson Dr., #301, Irvine, CA 92612-1212. (949) 752-2273 or (800) 404-9500. [email protected]. <http://www.longqt.org>.

European Long QT Syndrome Information Center. Ronnerweg 2, Nidau, 2560 Switzerland 04(132) 331-5835. jmettler @bielnews.ch. <http://www.bielnews.ch/cyberhouse/qt/qt.html>.

SADS Foundation. PO Box 58767, 508 East South Temple, Suite 20, Salt Lake City, UT 84102. (800) 786-7723. <http://www.sads.org>.

WEBSITES

"Genetics of Long QT Syndrome/Cardiac Arrest." DNASciences (2001). <http://my.webmd.com/content/article/3204.676>.

"Heart of the Matter." New Scientist (3 April 1999). <http://www.newscientist.com/ns/19990403/newstory11.html>.

Lehmann, Michael. "Gender Differences in Long QT–What Are They?" Cardiac Arrhythmias Research and Education Foundation, Inc.<http://www.longqt.com/lqts/genddif.asp.htm>.

Long QT Syndrome European Information Center. <http://www.qtsyndrome.ch/lqts.html>.

Moss, Arthur J. "The Long QT Syndrome and Pregnancy." Cardiac Arrhythmias Research and Education Foundation, Inc.<http://www.longqt.com/lqts/pregncy.asp.htm>.

"Study Links Abnormal Heart Rhythm to SIDS." MayoFoundation for Medical Education and Research. (16 August 2000). <http://www.mayohealth.org/home?id=HO00142>.

Vincent, G. Michael. An Overview of the Inherited Long QTSyndrome. (7 June 2000). <http://www.sads.org>.

Margaret Alic, PhD