Long QT syndrome

Many people with long QT syndrome have no signs or symptoms. When symptoms occur, they are generally caused by abnormal heart rhythms (arrhythmias), most commonly a form of ventricular tachycardia called Torsades de pointes (TdP). If the arrhythmia reverts to a normal rhythm spontaneously, the affected person may experience lightheadedness (known as presyncope) or faint. A fluttering sensation in the chest may precede fainting. Epilepsy is also associated with certain types of long QT syndrome. Some rare forms of long QT syndrome affect other parts of the body, leading to deafness in the Jervell and Lange-Nielsen form of the condition, and periodic paralysis in the Andersen–Tawil (LQT7) form. The strongest predictor of whether someone will develop TdP is whether they have experienced this arrhythmia or another form of cardiac arrest in the past. Those with LQTS who have experienced syncope without an ECG having been recorded at the time are also at higher risk, as syncope in these cases is frequently due to an undocumented self-terminating arrhythmia. While some have QT intervals that are very prolonged, others have only slight QT prolongation, or even a normal QT interval at rest (concealed LQTS). Those with the longest QT intervals are more likely to experience TdP, and a corrected QT interval of greater than 500 ms is thought to represent those at higher risk. Despite this, those with only subtle QT prolongation or concealed LQTS still have some risk of arrhythmias. ==Causes==

There are several subtypes of long QT syndrome. These can be broadly split into those caused by genetic mutations which those affected are born with, carry throughout their lives, and can pass on to their children (inherited or congenital long QT syndrome), and those caused by other factors which cannot be passed on and are often reversible (acquired long QT syndrome). Inherited (middle) and Jervell and Lange-Nielsen syndrome (bottom) Genetic abnormalities cause inherited or congenital long QT syndrome. LQTS can arise from variants in several genes, leading in some cases to quite different features. The common thread linking these variants is that they affect one or more ion currents leading to prolongation of the ventricular action potential, thus lengthening the QT interval. A less commonly seen form is Jervell and Lange-Nielsen syndrome, an autosomal recessive form of LQTS combining a prolonged QT interval with congenital deafness. Romano–Ward syndrome LQT1 is the most common subtype of Romano–Ward syndrome, responsible for 30 to 35% of all cases. The LQT2 subtype is the second-most common form of Romano–Ward syndrome, responsible for 25 to 30% of all cases. LQT6 is caused by variants in the KCNE2 gene responsible for the potassium channel beta subunit MiRP1 which generates the potassium current IKr. a protein involved in the parasympathetic modulation of the heart. The condition is inherited in an autosomal-dominant manner. It is caused by mutations in the KCNJ2'' gene which encodes the potassium channel protein Kir2.1. Timothy syndrome (LQT8) LQT8, also known as Timothy syndrome, combines a prolonged QT interval with fused fingers or toes (syndactyly). Abnormalities of the structure of the heart are commonly seen including ventricular septal defect, tetralogy of Fallot, and hypertrophic cardiomyopathy. The condition presents early in life and the average life expectancy is 2.5 years with death most commonly caused by ventricular arrhythmias. Many children with Timothy syndrome who survive longer than this have features of autism spectrum disorder. Timothy syndrome is caused by variants in the calcium channel Cav1.2 encoded by the gene CACNA1c. Table of associated genes The following is a list of genes associated with Long QT syndrome: Acquired Although long QT syndrome is often a genetic condition, a prolonged QT interval associated with an increased risk of abnormal heart rhythms can also occur in people without a genetic abnormality, commonly due to a side effect of medications. Drug-induced QT prolongation is often a result of treatment by antiarrhythmic drugs such as amiodarone and sotalol, antibiotics such as erythromycin, or antihistamines such as terfenadine. Other causes of acquired LQTS include abnormally low levels of potassium (hypokalaemia) or magnesium (hypomagnesaemia) within the blood. This can be exacerbated following a sudden reduction in the blood supply to the heart (myocardial infarction), low levels of thyroid hormone (hypothyroidism), and a slow heart rate (bradycardia). Anorexia nervosa has been associated with sudden death, possibly due to QT prolongation. The malnutrition seen in this condition can sometimes affect the blood concentration of salts such as potassium, potentially leading to acquired long QT syndrome, in turn causing sudden cardiac death. The malnutrition and associated changes in salt balance develop over a prolonged period, and rapid refeeding may further disturb the salt imbalances, increasing the risk of arrhythmias. Care must therefore be taken to monitor electrolyte levels to avoid the complications of refeeding syndrome. Factors that prolong the QT interval are additive, meaning that a combination of factors (such as taking a QT-prolonging drug and having low levels of potassium) can cause a greater degree of QT prolongation than each factor alone. This also applies to some genetic variants, which by themselves only minimally prolong the QT interval but can make people more susceptible to significant drug-induced QT prolongation. == Mechanisms ==

The various forms of long QT syndrome, both congenital and acquired, produce abnormal heart rhythms (arrhythmias) by influencing the electrical signals that coordinate individual heart cells. The common theme is a prolongation of the cardiac action potential – the characteristic pattern of voltage changes across the cell membrane that occur with each heartbeat. Under the right conditions, reactivation of these currents, facilitated by the sodium-calcium exchanger, can cause further depolarisation of the cell. Early afterdepolarisations may occur as single events, but may occur repeatedly leading to multiple rapid activations of the cell. Some research suggests that delayed afterdepolarisations (DADs), occurring after repolarisation has completed, may also play a role in long QT syndrome. This form of afterdepolarisation originates from the spontaneous release of calcium from the intracellular calcium store known as the sarcoplasmic reticulum, forcing calcium out of the cell through the sodium calcium exchanger in exchange for sodium, generating a net inward current. While there is strong evidence that the trigger for torsades de pointes comes from afterdepolarisations, it is less certain what sustains this arrhythmia. Some lines of evidence suggest that repeated afterdepolarisations from many sources contribute to the continuing arrhythmia. However, some suggest that the arrhythmia sustains through a mechanism known as re-entry. According to this model, the action potential prolongation occurs to a variable extent in different layers of the heart muscle, with longer action potentials in some layers than others. In response to a triggering impulse, the waves of depolarisation will spread through regions with shorter action potentials but block in regions with longer action potentials. This allows the depolarising wavefront to bend around areas of block, potentially forming a complete loop and becoming self-perpetuating. The twisting pattern on the ECG can be explained by the movement of the core of the re-entrant circuit in the form of a meandering spiral wave. == Diagnosis ==

with normal and prolonged QT intervals Diagnosing long QT syndrome is challenging. Whilst the hallmark of LQTS is prolongation of the QT interval, the QT interval is highly variable among both those who are healthy and those who have LQTS. This leads to overlap between the QT intervals of those with and without LQTS. 25% of those with genetically proven LQTS have a QT interval within the normal range. These investigations are most useful for identifying those with concealed congenital Type 1 LQTS 1 (LQT1) who have a normal QT interval at rest. While in healthy persons the QT interval shortens during exercise, in those with concealed LQT1, exercise or adrenaline infusion may lead to paradoxical prolongation of the QT interval, revealing the underlying condition. Both sets of guidelines agree that LQTS can also be diagnosed if an individual has a Schwartz score of greater than 3 or if a pathogenic genetic variant associated with LQTS is identified, regardless of QT interval. ==Treatment==

Those diagnosed with LQTS are usually advised to avoid drugs that can prolong the QT interval further or lower the threshold for TDP, lists of which can be found in public access online databases. In addition to this, two intervention options are known for individuals with LQTS: arrhythmia prevention and arrhythmia termination. Arrhythmia prevention Arrhythmia suppression involves the use of medications or surgical procedures that attack the underlying cause of the arrhythmias associated with LQTS. Since the cause of arrhythmias in LQTS is early afterdepolarizations (EADs), and they are increased in states of adrenergic stimulation, steps can be taken to blunt adrenergic stimulation in these individuals. These include administration of beta receptor blocking agents, which decreases the risk of stress-induced arrhythmias. Nadolol, a powerful non-selective beta blocker, has been shown to reduce the arrhythmic risk in all three main genotypes (LQT1, LQT2, and LQT3). While the most compelling indication is for those whose long QT syndrome is caused by defective sodium channels producing a sustained late current (LQT3), As the predominant action of mexiletine is on the early peak sodium current, there are theoretical reasons why drugs which preferentially suppress the late sodium current, such as ranolazine, may be more effective. Evidence that this is the case in the real world is limited. ICD implantation may be considered as a preventive step. ==Outcomes==

Genotype and QTc interval duration are the strongest predictors of outcome for patients with LQTS. have endorsed the use of independently validated risk score calculator, called 1-2-3-LQTS-Risk Calculator, which allows to calculate individual 5-year risk of life-threatening arrhythmic events. For people who experience cardiac arrest or fainting caused by LQTS and who are untreated, the risk of death within 15 years is around 50%. ==Epidemiology==

Inherited LQTS is estimated to affect between one in 2,500 and 7,000 people. ==History==

The first documented case of LQTS was described in Leipzig by Meissner in 1856, when a deaf girl died after her teacher yelled at her. Soon after being notified, the girl's parents reported that her older brother, also deaf, had previously died after a terrible fright. This was several decades before the ECG was invented, but is likely the first described case of Jervell and Lange-Nielsen syndrome. In 1957, the first case documented by ECG was described by Anton Jervell and Fred Lange-Nielsen, working in Tønsberg, Norway. Italian pediatrician Cesarino Romano, in 1963, and Irish pediatrician Owen Conor Ward, in 1964, separately described the more common variant of LQTS with normal hearing, later called Romano-Ward syndrome. The establishment of the International Long-QT Syndrome Registry in 1979 allowed numerous pedigrees to be evaluated comprehensively. This helped in detecting many of the genes involved. Transgenic animal models of the LQTS helped define the roles of various genes and hormones involved, and recently experimental pharmacological therapies to normalize the abnormal repolarization in animals were published. == References ==