Long QT Syndrome
Long QT syndrome
Long QT syndrome (LQTS) is the overarching term used to describe a family of genetic or acquired disorders that are characterized by irregular heartbeats caused by problems in the heart's electrical activity (cardiac arrhythmias). The cardiac arrhythmias of Long QT syndrome can lead to cardiac arrest and sudden death. The syndrome is characterized by a longer-than-normal QT interval on an electrocardiogram.
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 characteristic symptoms include seizures or fainting, often in response to stress, and long QT intervals found on an electrocardiogram.
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. Depolarization, or electrical activity that causes heart contraction, and repolarization are orchestrated by the flow of potassium, sodium, and calcium through the heart cell's ion channels. 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 period of relaxation or recovery called the QT interval after each heart contraction. 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, which means turning of the points. A normal heartbeat begins in the right atrium of the heart and progresses down to the ventricles. In ventricular tachycardia or torsade de pointes, 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 quickly, 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 seven or more genes. These genes encode proteins that form the ion channels in the heart. Depending on the other functions of the gene that is mutated, features beyond irregular heartbeats may occur in individuals affected by the different forms of LQTS. Although some mutations causing LQTS 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 antihistamines, 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, anorexia, or starvation can also result in LQTS. Additional medical issues, such as strokes, some neurological problems, or alcoholism , also can cause LQTS. However, since only certain individuals develop LQTS under these circumstances, multiple genetic factors also play a role in the acquired disorder.
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. Although new genetic mutations that cause LQTS are still being discovered, the majority of inherited LQTS cases result from mutations in KVLQT1 or KCNE1, causing LQT1, or mutations in HERG or KCNE2, causing LQT2.
Most types of LQTS are autosomal dominant genetic disorders : the genes that cause LQTS are carried on one of the 22 pairs of numbered autosomal chromosomes, rather than on the X or Y sex chromosomes. Furthermore, in autosomal dominant conditions, only one copy of the mutant, or nonworking, gene is necessary for the development of LQTS. 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.
Some types of LQTS are inherited in an autosomal recessive pattern. In an autosomal recessive pattern, two copies of the mutant, or nonworking, gene are needed to develop the symptoms of LQTS. In these cases, both parents each carry one copy of a mutant gene. Individuals with only one copy of a nonworking gene for a recessive condition are known as carriers and have no problems related to the condition. In fact, each person carries between five and 10 nonworking genes for harmful, recessive conditions. However, when two people with the same nonworking recessive gene have children together, there is a 25% chance, with each pregnancy, for the child to inherit two nonworking copies, one from each parent. That child then has no working copies of the gene and has the signs and symptoms associated with a recessive condition.
Long QT syndrome 1 and long QT syndrome 5
Long QT syndrome 1 (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 (11p15.5); KVLQT1 also is known as KCNQ1. The KVLQT1 gene codes a critical part of a voltage-gated potassium ion channel that helps the heart beat. Even if the KVLQT1 creates an abnormal potassium ion channel part, it can still join with the other parts of the channel. A potassium ion channel that is constructed with an abnormal part or sub-unit does not work as well as a channel formed of all normal parts. Most mutations in KVLQT1 causing LQT1 are passed down in an autosomal dominant pattern through the family; however, some mutations in this gene may be passed down in an autosomal recessive pattern. In these cases, LQTS is present only in individuals with two abnormal KVLQT1 genes, one inherited from each parent. The pattern of inheritance depends on which type of LQTS-causing mutation is present in the family because some mutations cause a potassium ion channel part that works better than other mutations. Mutation analysis of the KVLQT1 gene and/or a detailed medical family history can determine the inheritance pattern of LQT1 in a specific family.
The KCNE1 (MinK or IsK) gene on chromosome 21 codes for another critical part of the voltage-gated potassium ion channel that combines with the part encoded by KVLQT1. Together, they form the ion channel that is responsible for the heart's potassium current. The channel encoded in KCNE1 and KVLQT1 is a slow ion channel that starts working when the heart is in depolarization. Depolarization of the heart 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 a LQT1 form of LQTS; however, LQTS resulting from mutations in KCNE1 may also be referred to as long QT syndrome 5 (LQT5). Mutations in potassium channel genes reduce the number of functional potassium channels in the heart and lengthen the QT interval by delaying depolarization.
Jervell and Lange-Nielsen syndrome
Jervell and Lange-Nielsen syndrome (JLNS) is a specific autosomal recessive form of LQTS. In JLNS, an individual has inherited two copies of an abnormal KVLQT1 or KCNE1 gene: one inherited from the mother and the other from the father. The syndrome is characterized by congenital deafness as well as a prolonged QT interval.
Long QT syndrome 2 and long QT syndrome 6
Long QT syndrome 2 (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 (7q35-q36), encodes a protein part of another potassium ion channel found in the heart. Mutations in HERG result in loss of the potassium current called IKr.
Long QT syndrome 6 (LQT6) is caused by mutations in the KCNE2 gene. The KCNE2 or MiRP1 (for MinK-related) gene is located on chromosome 21 (21q22.1). The gene encodes a protein part that combines with the protein encoded by HERG to form a potassium ion channel used in the heart. Mutations in potassium channel genes reduce the number of functional potassium channels in the heart and lengthen the QT interval by delaying depolarization.
Long QT syndrome 3
Mutations in the SCN5A gene can result in an uncommon form of LQTS known as long QT syndrome 3 (LQT3). SCN5A, on the short arm of chromosome 3 (3p21), encodes a part of a cardiac sodium ion channel. Some mutations in this gene prevent the channel from being turned off or 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, which prolongs the action potential.
Brugada syndrome is caused by a mutation in SCN5A, located on the short arm of chromosome 3 (3p21). The type of mutation that causes Brugada decreases the flow of sodium ions into the cells and shortens the time of action potential. The symptoms of Brugada syndrome, which includes ventricular arrhythmia, cardiac arrest, and sudden death, are caused by the shortened action potential.
Long QT syndrome 4
Long QT syndrome 4 (LQT4) is most often referred to as sick sinus syndrome with bradycardia. LQT4 is associated with mutation in the ankyrin-B gene called ANK2, which is located on the long arm of chromosome 4 (4q25-q27). ANK2 plays a vital role in the organization of a sodium pump that exchanges sodium and calcium in and out of the heart. A mutation in the ANK2 gene reduces ability to get necessary proteins and calcium to the heart cells. Individuals with LQT4 have the typical cardiac dysfunction seen in LQTS. However, a long QT interval is not always seen in individuals with LQT4, so it is considered a condition distinct from classical long QT syndromes.
Long QT syndrome 7
Long QT syndrome 7 (LQT7) is also known as Andersen cardiodysrhythmic periodic paralysis, Andersen syndrome, periodic paralysis, potassium-sensitive cardiodysrhythmic type, and Andersen-Tawil syndrome. LQT7 is associated with mutations in the KCNJ2 gene located on the long arm of chromosome 17 (17q23.1q24.2). Mutations in KCNJ2 decrease the ability of a potassium channel in the heart to react to a specific important protein, called phosphatidylinositol 4,5-bisphosphate (PIP2), and move potassium in and out of the body's muscles. The movement of potassium in and out of the body's muscles allows movement of the arms, legs, and other muscles.
Long QT syndrome with syndactyly
Long QT syndrome with syndactyly is also known as Timothy syndrome. Long QT syndrome with syndactyly is caused by new mutations in the CACNA1C gene located on the short arm of chromosome 12 (12p13.3). Mutations in CACNA1C keep calcium ion channels open and pulling in calcium ions. By constantly pulling in calcium ions, repolarization is delayed and the chance for an irregular heart beat, or arrhythmia, is increased.
Other forms of LQTS
A small number of individuals with LQTS have mutations in more than one of the known genes and may have symptoms of multiple LQTS types. Other 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. Between 2000 and 2005, several large studies characterized the presence of gene variants or alleles in genes, including KCNA5, KCNQ1, KCNH2, KCNE1, and KCNE2, that help control the length of the QT interval.
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 originally thought. 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 drowning 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 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
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 showing any symptoms of the disease. At least one-third of the individuals carrying a gene variant that causes LQTS do not exhibit any symptoms. Sudden infant death syndrome (SIDS) claims the lives of one or two out of every 1,000 infants. In 1998, the results of the Multicenter Italian Study of Neonatal Electrocardiography and a SIDS study found that a large number of SIDS victims had prolonged QT intervals.
Common symptoms of LQTS include dizziness, sudden loss of consciousness or fainting spells (syncopes), or convulsive seizures. 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 (fast heart beat of the lower heart chambers) usually reverts spontaneously to a normal rhythm within one minute or less, and the individual regains consciousness. These symptoms may first appear 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, a fast change in posture, or during moments of excitement or stress.
Affected newborn infants and children under the age of three may exhibit slower than normal resting heart rates. Individuals with LQTS may experience irregular heartbeats accompanied by chest pain.
Symptoms of LQTS can 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. 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 LQT4 have the typical cardiac dysfunction seen in LQTS: slow heart beat (sinus node bradycardia) leading to the abnormal function of the body's natural pacemaker (sinus node dysfunction), severely abnormal heartbeat of the lower heart chambers (ventricular fibrillation), rapid heartbeat (ventricular tachycardia), and episodes of severely abnormal heartbeat in the heart's upper chambers (atrial fibrillation) in adulthood (though not childhood), and risk of sudden death. However, a long QT interval is not always seen in individuals with LQT4, so it is considered a condition distinct from classical long QT syndromes. Individuals with some of the variants of the KCNE2 gene that cause LQT6 may be adversely affected by exercise and some medications.
Individuals with LQT7 are affected by episodes in which they cannot move (potassium-sensitive periodic paralysis), heart problems, and unusual face and body features. The symptoms of LQT7 can include short stature, wide-spaced eyes (hypertelorism), low-set ears, small chin (hypoplastic mandible), palate abnormalities, curved fingers and toes (clinodactyly), fused fingers and toes (syndactyly), curved back (scoliosis ), periodic paralysis, long QT interval, abnormal heart beat in the upper and lower chambers of the heart, rapid heart beat, and sudden death.
Long QT syndrome with syndactyly is characterized by symptoms in multiple parts of the body that include lethal heart arrhythmias, webbing of fingers and toes, heart defects present at birth, immune deficiency, severe low blood sugar that comes and goes, developmental delays, and autism .
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 (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. 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, up to 12% of individuals with LQTS may show normal-appearing or borderline-normal QT intervals. 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.
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 individuals with LQTS may have low levels of potassium in their blood.
Some individuals with LQTS may be identified by the combination of the standard diagnostic measurement with ECG and physical examination. Long QT syndrome with syndactyly, LQT7, and Jervell and Lange-Nielsen syndrome have features, such as a hearing impairment, fused fingers, or facial features, that may lead to a diagnosis.
Currently, there is not a specific diagnostic test that can identify all cases of LQTS. The difficulty in developing a comprehensive test is due to the fact that more than 200 specific changes in many different genes have been found to be responsible for LQTS. Additionally, approximately half of the individuals diagnosed with LQTS do not carry any of the known genetic variations. 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-adrenergic blockers, or beta-blockers, are the most common treatment for the ventricular arrhythmia resulting from LQTS. Propranolol is the most frequently prescribed drug. It 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.
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.
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.
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.
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) are also 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.
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. Additionally, individuals with LQTS must avoid a very long list of drugs and medications that 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 have someone around them during moderate exercise. Family members may be advised to learn cardiopulmonary resuscitation (CPR) in case of cardiac arrest.
Individuals with LQTS require special attention and careful management before, during, and after surgery. In 2005, recommendations before surgery where developed, and include: monitoring baseline QT interval; using adequate amounts of beta-blocker medications, maintaining a quiet and calm environment; preparing a defibrillator to be available for immediate use; using premedications as needed; ensuring patient is adequately anesthetized before laryngoscopy and tracheal intubation to avoid sympathetic stimulation; and using of topical anesthesia before intubation. During the operation, recommendations include: monitoring the QT interval, keeping a quiet and calm environment, and avoiding patient hypothermia. Specific agents are recommended to be used for general anesthesia, including propofol for induction or as continuous infusion throughout, isoflurane as volatile agent of choice, vecuronium for muscle relaxation (dose appropriately to avoid pharmacologic reversal), and fentanyl for analgesia. After surgery, careful monitoring of the patient and their QT interval is recommended until the patient has recovered from anesthesia and the monitored QT interval has returned to baseline. It is also recommended to ensure adequate pain control after surgery.
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.
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 of irregular heartbeat 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.
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Dawn Jacob Laney, MS
Margaret Alic, PhD