long qt syndrome long qt syndrome long qt syndrome (lqts) is a condition affecting repolarization (relaxing) of the heart after a heartbeat, giving rise to an abnormally lengthy qt interval. it results in an increased risk of an irregular heartbeat which can result in fainting, drowning, seizures, or sudden death. these episodes can be triggered by exercise or stress. some rare forms of lqts are associated with other symptoms and signs including deafness and periods of muscle weakness. long qt syndromeecg showing typical pattern of inherited long qt syndrome (lqt1). a qt interval of >480 ms is considered abnormally long.specialtycardiologysymptomsfainting, hearing loss, seizurescomplicationssudden deathcausesgenetic, certain medications, low blood potassium, low blood calcium, heart failurerisk factorsfamily history of sudden deathdiagnostic methodelectrocardiogram (ekg), clinical findings, genetic testing differential diagnosisbrugada syndrome, arrhythmogenic right ventricular dysplasiatreatmentavoiding strenuous exercise, getting sufficient potassium, beta blockers, implantable cardiac defibrillatorfrequency≈ 1 in 7,000deaths≈3,500 a year (usa) long qt syndrome may be present at birth or develop later in life. the inherited form may occur by itself or as part of larger genetic disorder. onset later in life may result from certain medications, low blood potassium, low blood calcium, or heart failure. medications that are implicated include certain antiarrhythmics, antibiotics, and antipsychotics. lqts can be diagnosed using an electrocardiogram (ekg) if a corrected qt interval of greater than 480–500 milliseconds is found, but clinical findings, other ekg features, and genetic testing may confirm the diagnosis with shorter qt intervals. management may include avoiding strenuous exercise, getting sufficient potassium in the diet, the use of beta blockers, or an implantable cardiac defibrillator. for people with lqts who survive cardiac arrest and remain untreated, the risk of death within 15 years is greater than 50%. with proper treatment this decreases to less than 1% over 20 years. long qt syndrome is estimated to affect 1 in 7,000 people. females are affected more often than males. most people with the condition develop symptoms before they are 40 years old. it is a relatively common cause of sudden death along with brugada syndrome and arrhythmogenic right ventricular dysplasia. in the united states it results in about 3,500 deaths a year. the condition was first clearly described in 1957. signs and symptoms acquired 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 which may be preceded by a fluttering sensation in the chest. if the arrhythmia continues, the affected person may experience a cardiac arrest, which if untreated may lead to sudden death. those with lqts may also experience seizure-like activity (non-epileptic seizure) as a result of reduced blood flow to the brain during an arrhythmia. epilepsy is also associated with certain types of long qt syndrome. the arrhythmias that lead to faints and sudden death are more likely to occur in specific circumstances, in part determined by which genetic variant is present. while arrhythmias can occur at any time, in some forms of lqts arrhythmias are more commonly seen in response to exercise or mental stress (lqt1), in other forms following a sudden loud noise (lqt2), and in some forms during sleep or immediately upon waking (lqt3). 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. risk for arrhythmias while those with long qt syndrome have an increased risk of developing abnormal heart rhythms, the absolute risk of arrhythmias is very variable. 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. in addition to a history of arrhythmias, the extent to which the qt is prolonged predicts risk. 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. overall, every 10 ms increase in the corrected qt interval is associated with a 15% increase in arrhythmic risk. as the qt prolonging effects of both genetic variants and acquired causes of lqts are additive, those with inherited lqts are more likely to experience tdp if given qt prolonging drugs or if they experience electrolyte problems such as low blood levels of low potassium (hypokalaemia). similarly, those taking qt prolonging medications are more likely to experience tdp if they have a genetic tendency to a prolonged qt interval, even it this tendency is concealed. arrhythmias occur more commonly in drug-induced lqts if the medication in question has been rapidly given intravenously, or if high concentrations of the drug are present in the person's blood. the risk of arrhythmias is also higher if the person receiving the drug has heart failure, is taking digitalis, or has recently been cardioverted from atrial fibrillation. other risk factors for developing torsades de pointes among those with lqts include female sex, increasing age, pre-existing cardiovascular disease, and abnormal liver or kidney function. 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 electrocardiograms from a single family showing unaffected family member (top), romano ward syndrome (middle) and jervell and lange-nielsen syndrome (bottom). inherited, or congenital long qt syndrome, is caused by genetic abnormalities. 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. classification systems have been proposed to distinguish between subtypes of the condition based on the clinical features (and named after those who first described the condition) and subdivided by the underlying genetic variant. the commonest of these, accounting for 99% of cases, is romano–ward syndrome (genetically lqt1-6 and lqt9-16), an autosomal dominant form in which the electrical activity of the heart is affected without involving other organs. 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. other rare forms include andersen–tawil syndrome (lqt7) with features including a prolonged qt interval, periodic paralysis, and abnormalities of the face and skeleton; and timothy syndrome (lqt8) in which a prolonged qt interval is associated with abnormalities in the structure of the heart and autism spectrum disorder. romano–ward syndrome main article: romano–ward syndrome lqt1 is the most common subtype of romano–ward syndrome, responsible for 30 to 35% of all cases. the gene responsible, kcnq1, has been isolated to chromosome 11p15.5 and encodes the alpha subunit of the kvlqt1 potassium channel. this subunit interacts with other proteins (in particular, the mink beta subunit) to create the channel, which carries the delayed potassium rectifier current iks responsible for the repolarisation phase of the cardiac action potential. variants in kcnq1 that decrease iks (loss of function variants) slow the repolarisation of the action potential. this causes the lqt1 subtype of romano–ward syndrome when a single copy of the variant is inherited (heterozygous, autosomal dominant inheritance). inheriting two copies of the variant (homozygous, autosomal recessive inheritance) leads to the more severe jervell and lange–nielsen syndrome. conversely, variants in kcnq1 that increase iks lead to more rapid repolarisation and the short qt syndrome. the lqt2 subtype is the second-most common form of romano–ward syndrome, responsible for 25 to 30% of all cases. it is caused by variants in the kcnh2 gene (also known as herg) on chromosome 7 which encodes the potassium channel that carries the rapid inward rectifier current ikr. this current contributes to the terminal repolarisation phase of the cardiac action potential, and therefore the length of the qt interval. the lqt3 subtype of romano–ward syndrome is caused by variants in the scn5a gene located on chromosome 3p21–24. scn5a encodes the alpha subunit of the cardiac sodium channel, nav1.5, responsible for the sodium current ina which depolarises cardiac cells at the start of the action potential. cardiac sodium channels normally inactivate rapidly, but the mutations involved in lqt3 slow their inactivation leading to a small sustained 'late' sodium current. this continued inward current prolongs the action potential and thereby the qt interval. while some variants in scn5a cause lqt3, other variants can cause quite different conditions. variants causing a reduction in the early peak current can cause brugada syndrome and cardiac conduction disease, while other variants have been associated with dilated cardiomyopathy. some variants which affect both the early and late sodium current can cause overlap syndromes which combine aspects of both lqt3 and brugada syndrome. rare romano–ward subtypes (lqt4-6 and lqt9-16) lqt5 is caused by variants in the kcne1 gene responsible for the potassium channel beta subunit mink. this subunit, in conjunction with the alpha subunit encoded by kcnq1, is responsible for the potassium current iks which is decreased in lqts. lqt6 is caused by variants in the kcne2 gene responsible for the potassium channel beta subunit mirp1 which generates the potassium current ikr. variants that decrease this current have been associated with prolongation of the qt interval. however, subsequent evidence such as the relatively common finding of variants in the gene in those without long qt syndrome, and the general need for a second stressor such as hypokalaemia to be present to reveal the qt prolongation, has suggested that this gene instead represents a modifier to susceptibility to qt prolongation. some therefore dispute whether variants in kcne2 are sufficient to cause romano-ward syndrome by themselves. lqt9 is caused by variants in the membrane structural protein, caveolin-3. caveolins form specific membrane domains called caveolae in which voltage-gated sodium channels sit. similar to lqt3, these caveolin variants increase the late sustained sodium current, which impairs cellular repolarization. lqt10 is an extremely rare subtype, caused by variants in the scn4b gene. the product of this gene is an auxiliary beta-subunit (navβ4) forming cardiac sodium channels, variants in which increase the late sustained sodium current. lqt13 is caused by variants in girk4, a protein involved in the parasympathetic modulation of the heart. clinically, the patients are characterized by only modest qt prolongation, but an increased propensity for atrial arrhythmias. lqt14, lqt15 and lqt16 are caused by variants in the genes responsible for calmodulin (calm1, calm2, and calm3 respectively). calmodulin interacts with several ion channels and its roles include modulation of the l-type calcium current in response to calcium concentrations, and trafficking the proteins produced by kcnq1 and thereby influencing potassium currents. the precise mechanisms by which means these genetic variants prolong the qt interval remain uncertain. jervell and lange–nielsen syndrome main article: jervell and lange-nielsen syndromejervell and lange–nielsen syndrome (jlns) is a rare form of lqts inherited in an autosomal recessive manner. in addition to severe prolongation of the qt interval, those affected are born with severe sensorineural deafness affecting both ears. the syndrome is caused by inheriting two copies of certain variant in the kcne1 or kcnq1 genes. the same genetic variants lead to the lqt1 and lqt5 forms of romano-ward syndrome if only a single copy of the variant is inherited. jlns is generally associated with a higher risk of arrhythmias than most other forms of lqts. andersen–tawil syndrome (lqt7) main article: andersen–tawil syndrome lqt7, also known as andersen–tawil syndrome, is characterised by a triad of features – in addition to a prolonged qt interval,